Developing models of biological mechanisms, such as those involved in respiration in cells, often requires collaborative effort drawing upon techniques developed and information generated in different disciplines. Biochemists in the early decades of the 20th century uncovered all but the most elusive chemical operations involved in cellular respiration, but were unable to align the reaction pathways with particular structures in the cell. During the period 1940-1965 cell biology was emerging as a new discipline and made distinctive contributions to understanding the (...) role of the mitochondrion and its component parts in cellular respiration. In particular, by developing techniques for localizing enzymes or enzyme systems in specific cellular components, cell biologists provided crucial information about the organized structures in which the biochemical reactions occurred. Although the idea that biochemical operations are intimately related to and depend on cell structures was at odds with the then-dominant emphasis on systems of soluble enzymes in biochemistry, a reconceptualization of energetic processes in the 1960s and 1970s made it clear why cell structure was critical to the biochemical account. This paper examines how numerous excursions between biochemistry and cell biology contributed a new understanding of the mechanism of cellular respiration. (shrink)

Aerobic mitochondria serve as the power sources of eukaryotes by producing ATP through oxidative phosphorylation (OXPHOS). The enzymes involved in OXPHOS are multisubunit complexes encoded by both nuclear and mitochondrial DNA. Thus, regulation of respiration is necessarily a highly coordinated process that must organize production, assembly and function of mitochondria to meet an organism's energetic needs. Here I review the role of OXPHOS in metabolic adaptation and diversification of higher animals. On a physiological timescale, endocrine‐initiated signaling pathways allow organisms (...) to modulate respiratory enzyme concentration and function under changing environmental conditions. On an evolutionary timescale, mitochondrial enzymes are targets of natural selection, balancing cytonuclear coevolutionary constraints against physiological innovation. By synthesizing our knowledge of biochemistry, physiology and evolution of respiratory regulation, I propose that we can now explore questions at the interface of these fields, from molecular translation of environmental cues to selection on mitochondrial haplotype variation. BioEssays 28: 890–901, 2006. © 2006 Wiley periodicals, Inc. (shrink)

The mitochondrion is known as the “powerhouse” of eukaryotic cells since it is the main site of adenosine 5′‐triphosphate (ATP) production. Using a temperature‐sensitive fluorescent probe, it has recently been suggested that the stray free energy, not captured into ATP, is potentially sufficient to sustain mitochondrial temperatures higher than the cellular environment, possibly reaching up to 50 °C. By 50 °C, some DNA and mitochondrial proteins may reach their melting temperatures; how then do these biomolecules maintain their structure (...) and function? Further, the production of reactive oxygen species (ROS) accelerates with temperature, implying higher oxidative stresses in the mitochondrion than generally appreciated. Herein, it is proposed that mitochondrial heat shock proteins (particularly Hsp70), in addition to their roles in protein transport and folding, protect mitochondrial proteins and DNA from thermal and ROS damage. Other thermoprotectant mechanisms are also discussed. (shrink)

Mitochondrial replacement techniques have the potential to allow prospective parents who are at risk of passing on debilitating or even life-threatening mitochondrial disorders to have healthy children to whom they are genetically related. Ethical concerns have however been raised about these techniques. This article focuses on one aspect of the ethical debate, the question of whether there is any moral difference between the two types of MRT proposed: Pronuclear Transfer and Maternal Spindle Transfer. It examines how questions of (...) identity impact on the ethical evaluation of each technique and argues that there is an important difference between the two. PNT, it is argued, is a form of therapy based on embryo modification while MST is, instead, an instance of selective reproduction. The article's main ethical conclusion is that, in some circumstances, there is a stronger obligation to use PNT than MST. (shrink)

This article argues that two forms of mitochondrial replacement therapy, maternal spindle transfer and pro-nuclear transfer, are not therapies at all because they do not treat children who are coming into existence. Rather, these technologies merely create healthy children where none was inevitable. Even if creating healthy lives has some value, it is not to be confused with the medical value of a cure or therapy. The article addresses a recent Bioethics article, ‘Mitochondrial Replacement: Ethics and Identity,’ by (...) Wrigley, Wilkinson, and Appleby, who argue that PNT is morally favorable to MST due to the Non-Identity Problem. Wrigley et al. claim that PNT, since it occurs post-conception, preserves the identity of the resulting child, whereas MST, since it occurs pre-conception, is an identity-altering technique. As such, a child born with mitochondrial disease could complain that her parents failed to use PNT, but not MST. The present article argues that the authors are mistaken: both MST and PNT are identity-affecting techniques. But this is of little matter, for we should be cautious in drawing any moral conclusions from the application of the Non-Identity Problem to cases. The article then argues that the authors are mistaken in inferring that PNT is a type of embryonic cure or therapy for children with mitochondrial disease. The article cautions against the mistaken life-saving rhetoric that is common in bioethics discussions of MRTs. (shrink)

Mitochondrial replacement techniques are intended to avoid the transmission of mitochondrial diseases from mother to child. MRT represent a potentially powerful new biomedical technology with ethical, policy, economic and social implications. Among other ethical questions raised are concerns about the possible effects on the identity of children born from MRT, their families, and the providers or donors of mitochondria. It has been suggested that MRT can influence identity directly, through altering the genetic makeup and physical characteristics of the (...) child, or indirectly through changing the child's experience of disease, and by generating novel intrafamilial relationships that shape the sense of self. In this article I consider the plausibility and ethical implications of these proposed identity effects, but I focus instead on a third way in which identity may be affected, through the mediating influence of the wider social world on MRT effects on identity. By taking a narrative approach, and examining the nature and availability of identity narratives, I conclude that while neither direct genetic nor indirect experiential effects can be excluded, social responses to MRT are more likely to have a significant and potentially damaging influence on the generation of MRT children's narratives of identity. This conclusion carries some implications for the collective moral responsibility we hold to ensure that MRT, if implemented, are practised in ethically justifiable ways. (shrink)

Mitochondrial/nuclear transfer (M/NT) to avoid the transmission of serious mitochondrial disease raises complex and challenging ethical, legal and social issues (ELSI). In February 2015, the United Kingdom became the first country in the world to legalize M/NT, making the heated debate surrounding this technology even more relevant. This critical interpretive review identified 95 relevant papers discussing the ELSI of M/NT, including original research articles, government-commissioned reports, editorials, letters to editors and research news. The review presents and synthesizes the (...) arguments present in the literature in relation to the most commonly raised themes: terminology; identity, relationships and parenthood; potential harm; reproductive autonomy; available alternatives; consent; impact on specific interest groups; resources; “slippery slope”; creation, use and destruction of human embryos; and beneficence. The review concludes by identifying those ELSI that are specific to M/NT and by calling for follow-up longitudinal clinical and psychosocial research in order to equip future ELSI debate with empirical evidence. (shrink)

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age‐related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. (...) Sustained stress induces a selective autophagy – termed mitophagy – and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context‐ and time‐dependent network of mitochondrial quality control that is implicated in healthy aging. (shrink)

Mitochondrial replacement techniques, known in the popular media as 'three-parent' or 'three-person' IVFs, have the potential to enable women with mitochondrial diseases to have children who are genetically related to them but without such diseases. In the debate regarding whether MRTs should be made available, an issue that has garnered considerable attention is whether MRTs affect the characteristics of an existing individual or whether they result in the creation of a new individual, given that MRTs involve the genetic (...) manipulation of the germline. In other words, do MRTs affect the qualitative identity or the numerical identity of the resulting child? For instance, a group of panelists on behalf of the UK Human Fertilisation and Embryology Authority has claimed that MRTs affect only the qualitative identity of the resulting child, while the Working Group of the Nuffield Council on Bioethics has argued that MRTs would create a numerically distinct individual. In this article, I shall argue that MRTs do create a new and numerically distinct individual. Since my explanation is different from the NCOB's explanation, I shall also offer reasons why my explanation is preferable to the NCOB's explanation. (shrink)

The classification of techniques used in mitochondrial donation, including their role as purported germ-line gene therapies, is far from clear. These techniques exhibit characteristics typical of a variety of classifications that have been used in both scientific and bioethics scholarship. This raises two connected questions, which we address in this paper: how should we classify mitochondrial donation techniques?; and what ethical implications surround such a classification? First, we outline how methods of genetic intervention, such as germ-line gene therapy, (...) are typically defined or classified. We then consider whether techniques of mitochondrial donation fit into these, whether they might do so with some refinement of these categories, or whether they require some other approach to classification. To answer the second question, we discuss the relationship between classification and several key ethical issues arising from mitochondrial donation. We conclude that the properties characteristic of mitochondrial inheritance mean that most mitochondrial donation techniques belong to a new sub-class of genetic modification, which we call ‘conditionally inheritable genomic modification’. (shrink)

Mitochondrial shape change, brought about by molecules that promote either fission or fusion between individual mitochondria, has been documented in several model systems. However, the deeper significance of mitochondrial shape change has only recently begun to emerge: among others, it appears to play a role in the regulation of cell proliferation. Here, I review the emerging interplay between mitochondrial fission‐fusion components with cell cycle regulatory machineries and how that may impact cell differentiation. Regulation of mitochondrial shape (...) may modulate mitochondrial metabolism and/or energetics to promote crosstalk between signaling components and the cell cycle machinery. Focused research in this area will reveal the exact role of mitochondria in development and disease, specifically in stem cell regulation and tumorigenesis. Such research may also reveal whether and how the endosymbiotic event that gave rise to the mitochondrion was crucial for the evolution of cell cycle regulatory mechanisms in eukaryotes that are absent in prokaryotes. (shrink)

In February 2015 the UK became the first country to legalise high-profile mitochondrial replacement techniques, which involve the creation of offspring using genetic material from three individuals. The aim of these new cell reconstruction techniques is to prevent the transmission of maternally inherited mitochondrial disorders to biological offspring. During the UK debates, MRTs were often positioned as a straightforward and unique solution for the ‘eradication’ of mitochondrial disorders, enabling hundreds of women to have a healthy, biologically-related child. (...) However, many questions regarding future applications and potential users remain. Drawing on a current qualitative study on reproductive choices in the context of mitochondrial disorders, this article illustrates how the potential limitations of MRTs have been obscured in public debates by contrasting the claims made about the future beneficiaries with insights from families affected by mitochondrial disorders and medical experts. The analysis illuminates the complex choices with which families and individuals affected by mitochondrial disorders are faced, which have thus far remained invisible. An argument is presented for improved information for the public as well as an intensification of critical empirical research around the complex and specific needs of future beneficiaries of new reproductive biotechnologies. (shrink)

We review a recent paper in Genome Research by Guantes et al. showing that nuclear gene expression is influenced by the bioenergetic status of the mitochondria. The amount of energy that mitochondria make available for gene expression varies considerably. It depends on: the energetic demands of the tissue; the mitochondrial DNA (mtDNA) mutant load; the number of mitochondria; stressors present in the cell. Hence, when failing mitochondria place the cell in energy crisis there are major effects on gene expression (...) affecting the risk of degenerative diseases, cancer and ageing. In 2015 the UK parliament approved a change in the regulation of IVF techniques, allowing “Mitochondrial replacement therapy” to become a reproductive choice for women at risk of transmitting mitochondrial disease to their children. This is the first time that this technique will be available. Therefore understanding the interaction between mitochondria and the nucleus has never been more important. (shrink)

Mitochondrial replacement therapy (MRT), also called nuclear genome transfer and mitochondrial donation, is a new technique that can be used to prevent the transmission of mitochondrial DNA diseases. Apart from the United Kingdom, the first country to approve MRT in 2015, Australia became the second country with a clear regulatory path for the clinical applications of this technique in 2021. The rapidly evolving clinical landscape of MRT makes the elaboration and evaluation of the responsible use of this (...) technology a pressing matter. As jurisdictions with less strict or non-existent reproductive laws are continuing to use MRT in the clinical context, the need to address the underlying ethical issues surrounding MRT’s clinical translation is fundamental. (shrink)

Much research has focused on the effects of pathogenic mitochondrial mutations on health. Notwithstanding, the mechanisms regulating the link between these mutations and their effects remain elusive in several cases. Here, we propose that certain mitochondrial mutations may disrupt function of a set of mitochondrial‐transcribed small RNAs, perturbing communication between mitochondria and nucleus, leading to disease. Our hypothesis synthesises two lines of supporting evidence. First, several mitochondrial mutations cannot be directly linked to effects on energy production (...) or protein synthesis. Second, emerging studies have described the existence of small RNAs encoded by the mitochondria and proposed their involvement in RNA interference. We present a roadmap to testing this hypothesis. (shrink)

Mitochondrial bioenergetics plays a key role in multiple basic cellular processes, such as energy production, nucleotide biosynthesis, and iron metabolism. It is an essential system for animals' life and death (apoptosis) and it is required for embryo development. This, in conjunction with its being subjected to adaptive processes in multiple species and its gene products being involved in the formation of reproductive barriers in animals, raises the possibility that mitochondrial bioenergetics could be a candidate genetic mechanism of speciation. (...) Here, we discuss genetic and biochemical evidence for the possible involvement of this unique system, encoded by two genomes (the mitochondrial and nuclear genomes), that differ by an order of magnitude in their mutation rates in processes leading to speciation events. (shrink)

This paper argues that the biochemistry of memory consolidation provides valuable model systems for exploring the multiple realization of psychological states.

Currently in the United Kingdom, anyone donating gametes has the status of an open-identity donor. This means that, at the age of 18, persons conceived with gametes donated since April 1, 2005 have a right to access certain pieces of identifying information about their donor. However, in early 2015, the UK Parliament approved new regulations that make mitochondrial donors anonymous. Both mitochondrial donation and gamete donation are similar in the basic sense that they involve the contribution of gamete (...) materials to create future persons. Given this similarity, this paper presumes that both types of donor should be treated the same and made open-identity under the law, unless there is a convincing argument for treating them differently. I argue that none of the existing arguments that have been made so far in favor of mitochondrial donor anonymity are convincing and mitochondrial donors should therefore be treated as open-identity donors under UK law. (shrink)

Mitochondrial replacement technology (MRT) is an emerging and complex bioethical issue. This treatment aims to eliminate maternal inherited mitochondrial DNA (mtDNA) disorders. For Muslims, its introduction affects every aspect of human life, especially the five essential interests of human beings—namely, religion, life, lineage, intellect, and property. Thus, this technology must be assessed using a comprehensive and holistic approach addressing these human essential interests. Consequently, this article analyses and assesses tri-parent baby technology from the perspective of Maqasidic bioethics—that is, (...) Islamic bioethics based on the framework of Maqasid al-Shariah. Using this analysis, this article suggests that tri-parent baby technology should not be permitted for Muslims due to the existence of third-party cell gametes which lead to lineage mixing and due to the uncertain safety of the therapy itself and because the major aim of the technology is to fulfil the affected couples interest to conceive their own genetically healthy child, not to treat and cure mtDNA disorders sufferers. (shrink)

The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK (...) and BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration. (shrink)

Heterogeneity in mitochondrial content has been previously suggested as a major contributor to cellular noise, with multiple studies indicating its direct involvement in biomedically important cellular phenomena. A recently published dataset explored the connection between mitochondrial functionality and cell physiology, where a non‐linearity between mitochondrial functionality and cell size was found. Using mathematical models, we suggest that a combination of metabolic scaling and a simple model of cell death may account for these observations. However, our findings also (...) suggest the existence of alternative competing hypotheses, such as a non‐linearity between cell death and cell size. While we find that the proposed non‐linear coupling between mitochondrial functionality and cell size provides a compelling alternative to previous attempts to link mitochondrial heterogeneity and cell physiology, we emphasise the need to account for alternative causal variables, including cell cycle, size, mitochondrial density and death, in future studies of mitochondrial physiology. (shrink)

Mitochondrial genomes represent relict bacterial genomes derived from a progenitor α‐proteobacterium that gave rise to all mitochondria through an ancient endosymbiosis. Evolution has massively reduced these genomes, yet despite relative simplicity their organization and expression has developed considerable novelty throughout eukaryotic evolution. Few organisms have reengineered their mitochondrial genomes as thoroughly as the protist lineage of dinoflagellates. Recent work reveals dinoflagellate mitochondrial genomes as likely the most gene‐impoverished of any free‐living eukaryote, encoding only two to three proteins. (...) The organization and expression of these genomes, however, is far from the simplicity their gene content would suggest. Gene duplication, fragmentation, and scrambling have resulted in an inflated and complex genome organization. Extensive RNA editing then recodes gene transcripts, and trans‐splicing is required to assemble full‐length transcripts for at least one fragmented gene. Even after these processes, messenger RNAs (mRNAs) lack canonical start codons and most transcripts have abandoned stop codons altogether. (shrink)

News about the first baby born after a mitochondrial replacement technique (MRT; specifically maternal spindle transfer) broke on September 27, 2016 and, in a matter of hours, went global. Of special interest was the fact that the mitochondrial replacement procedure happened in Mexico. One of the scientists behind this world first was quoted as having said that he and his team went to Mexico to carry out the procedure because, in Mexico, there are no rules. In this paper, (...) we explore Mexico's rule of law in relation to mitochondrial replacement techniques and show that, in fact, certain instances of MRTs are prohibited at the federal level and others are prohibited at the state level. According to our interpretation of the law, the scientists behind this first successful MRT procedure broke federal regulations regarding assisted fertilization research. (shrink)

Mitochondrial replacement techniques are designed to allow couples to have children without passing on mitochondrial diseases. Recently, Giulia Cavaliere and César Palacios-González argued that prospective parents have the right to use MRTs to pursue genetic relatedness, such that some same-sex couples and/or polygamous triads could use the process to impart genetic relatedness between a child and more of its caregivers. Although MRTs carry medical risks, Cavaliere and Palacios-González contend that because MRTs are identity-affecting, they do not cause harm (...) to an existing human being, and our intuitions otherwise arise from the non-identity problem. Here, I review several attempts to address the non-identity problem, and propose a solution to the problem. Furthermore, I argue that regardless of one’s stance on whether MRTs are identity-affecting, the use of MRTs to pursue genetic relatedness alone falls outside the scope of the medical profession, as they involve substantive medical risk for no medical benefit. (shrink)

Several objections against the morality of researching or employing mitochondrial replacement techniques have been advanced recently. In this paper, I examine three of these objections and show that they are found wanting. First I examine whether mitochondrial replacement techniques, research and clinical practice, should not be carried out because of possible harms to egg donors. Next I assess whether mitochondrial replacement techniques should be banned because they could affect the study of genealogical ancestry. Finally, I examine the (...) claim that mitochondrial replacement techniques are not transferring mitochondrial DNA but nuclear DNA, and that this should be prohibited on ethical grounds. (shrink)

In this article, I draw on research carried out in Europe, primarily in Germany, on patients’ and scientists’ perspectives on mitochondrial replacement techniques in order to explore some of the complexities related to collective representation in health governance, which includes the translation of emerging technologies into clinical use. Focusing on observations, document analyses, and interviews with eight mitochondrial disease patient organization leaders, this contribution extends our understanding of the logic and meanings behind the ways in which patient participation (...) and collective representation in health governance initiatives take shape. My findings highlight the ways in which a commitment to a global mitochondrial disease patient community and a sense of patient solidarity influence expressions of support with regard to legalizing mitochondrial replacement techniques. My analyses illustrate how normative practices and expectations of participatory governance potentially foreclose opportunities for sustained collective patient engagement with the complex ethical, social, and political dimensions of emerging technologies and may silence diverse and potentially dissenting embodied and lived responses to the prospects of particular technological developments. (shrink)

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or (...) disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import. (shrink)

Mitochondria, the powerhouses of our cells, are essential to life. Normal mitochondrial function is achieved through the cooperative interaction of the nuclear and mitochondrial genomes. New IVF approaches intended to circumvent devastating mitochondrial disease look set to change the ancient pattern of mtDNA inheritance and interaction with unknown consequences.

Mitochondrial replacement techniques (MRTs) usually aim to prevent the genetic transmission of maternally inherited mitochondrial diseases. Until now, only the UK and Australia have implemented specific legal regulations of MRTs. In both countries, clinical trials on these techniques are only permissible for cases with a high risk of severe mitochondrial disease in the offspring. However, these techniques can also be applied to treat infertility, especially for older women with impaired oocyte quality. In some countries without legal regulation (...) of these techniques, MRTs are already offered for this purpose. Yet, this application of MRTs has received insufficient attention in the bioethical literature so far.In this paper, I examine whether there are ethical reasons to prohibit trials on MRTs in the context of infertility when they are permitted for preventing mitochondrial disease. Allowing MRTs in one context but not the other might be justified either because their application in the context of mitochondrial disease (1) is supported by a more convincing evidence base, (2) has a higher potential benefit or (3) has a lower risk. I compare both applications of MRTs with respect to these three factors. I conclude that there is no convincing reason to prohibit clinical trials on MRTs for infertility when they are permitted in the context of mitochondrial disease. (shrink)

The human Y chromosome contains very low levels of nucleotide variation. It has been variously hypothesized that this invariance reflects historic reductions in the human male population, a very recent common ancestry, a slow rate of molecular evolution, an inability to evolve adaptively, or frequent selective sweeps acting on genes borne on the Y chromosome. We propose an alternative theory in which human Y chromosome evolution is driven by mutations in the maternally inherited mitochondrial genome, which impair male fertility (...) and ultimately lead to a reduction in the effective population size (Ne) and consequently the variability of the Y chromosome. BioEssays 24:275–279, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10062. (shrink)

In this paper, we argue that lesbian couples who wish to have children who are genetically related to both of them should be allowed access to mitochondrial replacement techniques. First, we provide a brief explanation of mitochondrial diseases and MRTs. We then present the reasons why MRTs are not, by nature, therapeutic. The upshot of the view that MRTs are non-therapeutic techniques is that their therapeutic potential cannot be invoked for restricting their use only to those cases where (...) a mitochondrial DNA disease could be ‘cured’. We then argue that a positive case for MRTs is justified by an appeal to reproductive freedom, and that the criteria to access these techniques should hence be extended to include lesbian couples who wish to share genetic parenthood. Finally, we consider a potential objection to our argument: that the desire to have genetically related kin is not a morally sufficient reason to allow lesbian couples to access MRTs. (shrink)

Molecular genetic data have greatly improved our ability to test hypotheses about human evolution. During the past decade, a large amount of nuclear and mitochondrial data have been collected from diverse human populations. Taken together, these data indicate that modern humans are a relatively young species. African populations show the largest amount of genetic diversity, and they are the most genetically divergent population. Modern human populations expanded in size first on the African continent. These findings support a recent African (...) origin of modern humans, but this conclusion should be tempered by the possible effects of factors such as gene flow, population size differences, and natural selection. BioEssays 20:126–136, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Inner membranes of mitochondria are extensively folded, forming cristae. The observed overall correlation between efficient eukaryotic ATP generation and the area of internal mitochondrial inner membranes both in unicellular organisms and metazoan tissues seems to explain why they evolved. However, the crucial use of molecular oxygen (O2) as final acceptor of the electron transport chain is still not sufficiently appreciated. O2 was an essential prerequisite for cristae development during early eukaryogenesis and could be the factor allowing cristae retention upon (...) loss of mitochondrial ATP generation. Here I analyze illuminating bacterial and unicellular eukaryotic examples. I also discuss formative influences of intracellular O2 consumption on the evolution of the last eukaryotic common ancestor (LECA). These considerations bring about an explanation for the many genes coming from other organisms than the archaeon and bacterium merging at the start of eukaryogenesis. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Feminist Studies 47, no. 1. © 2021 by Bettina Judd 13 mitochondrial eve brainstorming the archive Bettina Judd what if we were to recover the first utterance of our selves? before black (but happen to be, in this moment of looking back, black.) before african (or african descended. from a place that would be called africa. from the first large place surrounded by waters.) before woman (and all (...) of the lies told therein.) what would we be? would we able to utter our own names? would i hear myself when called if i ever recovered me? -*the archive would be my dreams the intensity of elders’ eyes things that could not be said lest we all fall apart where shattered in the first place, the first time. uncover what? my marrow? this pelvic bone you once called home? you a child of children, a memory-premonition 14 Bettina Judd why you want so bad to remember all the things i’ve willfully forgotten? the hungers i’ve stuffed with human flesh? the joys i’ve chosen to live and in living would not write them down? uncover what? go. live. be a forest of your own dreams. be a mystery for your own children... (shrink)

Since the human mitochondrial genome was characterised and sequenced in 1981(1), it has been viewed as the likely site of genetic diseases showing a maternal inheritance pattern and associated with defects of the respiratory chain, such as the mitochondrial myopathies (MMs)†(2). The properties that make it a candidate for the source of such conditions are that it encodes polypeptides involved in electron transport(3,4) and that it is maternally inherited(5). However, several of the mtDNA diseases only fulfill one or (...) other of these criteria: the first group of mtDNA diseases showed Only sporadic deletions(6,7), and the first point mutation in Leber's Hereditary Optic Neuropathy(8) (LHON) is not associated with a clear biochemical defect. Furthermore, it is now clear that both autosomal dominant(9) and probably recessive(10) nuclear genes can cause abnormalities of mtDNA. Each of these major groups will be considered in turn. (shrink)

In the 1920s, scientists at the University of Cambridge’s Sir William Dunn Institute of Biochemistry made major contributions to the emerging discipline of biochemistry while also devoting considerable time and energy to the production of a humor journal entitled Brighter Biochemistry. Although humor is frequently regarded as peripheral to the work of science, the journal provides an opportunity to understand how it contributes to the social infrastructure of scientific communities as modern workplaces. Taking methodological cues from cultural (...) history, ethnography, and humor studies, this essay conducts a close and contextual reading of Brighter Biochemistry. This reading demonstrates how humor served as a central means through which members of the Dunn confronted workplace issues, including creating cooperative work teams, responding to gender discrimination, addressing funding anxiety, and defining professional identity. These conclusions provide a new perspective on the well-documented history of the Dunn and also offer a model for how historians of science can approach humor when its traces are encountered in other settings. (shrink)

Mitochondrial function and biogenesis depend on the transport of a large variety of proteins, ions, and metabolites across the two surrounding membranes. While several specific transporters are present in the inner membrane, transport processes across the outer membrane are less understood. Recent studies reveal that the number of outer membrane channels and their transport mechanisms are more diverse than originally thought. Four protein‐conducting channels promote transport of distinct sets of precursor proteins across and into the outer membrane. The voltage‐dependent (...) anion channel (VDAC) forms the major channel for small hydrophilic molecules. In addition, three channels with yet unknown substrate specificity exist in the outer membrane. In this review, we outline the emerging functional diversity, selectivity, and regulation of mitochondrial outer membrane channels. The presence of several channel‐forming proteins challenges the traditional view that the outer membrane forms an unspecific size‐exclusion filter for the flux of small hydrophilic molecules. (shrink)

Mitochondria contain a molecular genetic system to express the 13 protein components of the electron transport system encoded in the mitochondrial genome (mtDNA). Defects in the function of this system result in some diaseases, many of which are multisystem disorders, prominently involving highly aerobic, postmitotic tissues. These defects can be caused by large‐scale rearrangements of mtDNA, by point mutations, or by nuclear gene mutations resulting in abnormalities in mtDNA. Although any of these mutations would be expected to produce a (...) similar clinical phenotype by compromising oxidative phosphorylation, the surprising and puzzling result is that different clinical phenotypes are generally associated with specific mtDNA mutations. Moreover, the same mutation can produce a distinct clinical phenotype in different individuals or pedigrees. MtDNA rearrangements are also found in aged individuals, but at a subclinical level, suggesting that normal and pathological processes can differ by the effect of genetic or environmental factors on the error rate of mtDNA replication. (shrink)

Since mitochondrial replacement techniques were developed and clinically introduced in the United Kingdom, there has been much discussion of whether these lead to children borne of three parents. In the UK, the regulation of MRT has dealt with this by stipulating that egg donors for the purposes of MRT are not genetic parents even though they contribute mitochondrial DNA to offspring. In this paper, I examine the way that the Human Fertilisation and Embryology Act in the UK manages (...) the question of parentage. I argue that the Act breaks the link typically made between genetic causation and genetic parenthood by redefining genetic causation solely in terms of nuclear genetics. Along with this, mtDNA is construed as a kind of supplement to the nuclear family. Drawing on the account of the supplement developed by Jacques Derrida, I argue that mtDNA and the women who donate it are seen as both essential to establishing the nuclear family but also exterior to and insignificant for it. (shrink)

MPZL3 is a nuclear‐encoded, mitochondrially localized, immunoglobulin‐like V‐type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, an organ transformation process that is also governed by peripheral clock gene activity and PPARγ. Given the phenotype similarities and differences between Mpzl3 and Pparγ knockout mice, we propose that MPZL3 serves as a signaling hub (...) that is regulated by core clock gene products and/or PPARγ to translate signals from these nuclear transcription factors to the mitochondria to modulate circadian and metabolic regulation. Conservation between murine and human MPZL3 suggests that human MPZL3 may have similarly complex functions in health and disease. We summarize current knowledge and discuss future directions to elucidate the full spectrum of MPZL3 functions in mammalian physiology. (shrink)

The United Kingdom is the first and so far only country to pass explicit legislation allowing for the licensed use of the new reproductive technology known as mitochondrial replacement therapy. The techniques used in this technology may prevent the transmission of mitochondrial DNA diseases, but they are controversial because they involve the manipulation of oocytes or embryos and the transfer of genetic material. Some commentators have even suggested that MRT constitutes germline genome modification. All eyes were on the (...) United Kingdom as the most likely location for the first MRT birth, so it was a shock when, on September 27, 2016, an announcement went out that the first baby to result from use of the intervention had already been born. In New York City, United States-based scientist John Zhang used maternal spindle transfer to generate five embryos for a woman carrying oocytes with deleterious mutations of the mitochondrial DNA. Zhang then shipped the only euploid embryo to Mexico, where it was transferred to the mother's uterus. Zhang's team's travel across international borders to carry out experimental procedures represents a form of scientific tourism that has not been properly ethically explored; it can, however, have seriously detrimental effects for developing countries. (shrink)

Neither the pathogenesis nor the aetiology of Down's syndrome (DS) are clearly understood. Numerous studies have examined whether clinical features of DS are a consequence of specific chromosome 21 segments being triplicated. There is no evidence, however, that individual loci are responsible, or that the oxidative damage in DS could be solely explained by a gene dosage effect. Using astrocytes and neuronal cultures from DS fetuses, a recent paper shows that altered metabolism of the amyloid precursor protein and oxidative stress (...) result from mitochondrial dysfunction.1 These findings are consistent with considerable data implicating the role of the mitochondrial genome in DS pathogenesis and aetiology. BioEssays 24:681–684, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Schizophrenia (SCZ) is a severe neurodevelopmental disorder affecting 1% of populations worldwide with a grave disability and socioeconomic burden. Current antipsychotic medications are effective treatments for positive symptoms, but poorly address negative symptoms and cognitive symptoms, warranting the development of better treatment options. Further understanding of SCZ pathogenesis is critical in these endeavors. Accumulating evidence has pointed to the role of mitochondria and metabolic dysregulation in SCZ pathogenesis. This review critically summarizes recent studies associating a compromised mitochondrial function with (...) people with SCZ, including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cell studies. This review also discusses animal models with mitochondrial dysfunction resulting in SCZ‐relevant neurobehavioral abnormalities, as well as restoration of mitochondrial function as potential therapeutic targets. Further understanding of mitochondrial dysfunction in SCZ may open the door to develop novel therapeutic strategies that can address the symptoms that cannot be adequately addressed by current antipsychotics alone. (shrink)

A recent paper by Nisoli et al.1 provides the first evidence that elevated levels of nitric oxide (NO) stimulate mitochondrial biogenesis in a number of cell lines via a soluble guanylate‐cyclase‐dependent signaling pathway that activates PGC1α (peroxisome proliferator‐activated receptor γ coactivator‐1α), a master regulator of mitochondrial content. These results raise intriguing possibilities for a role of NO in modulating mitochondrial content in response to physiological stimuli such as exercise or cold exposure. However, whether this signaling cascade represents (...) a widespread mechanism by which mammalian tissues regulate mitochondrial content, and how it might integrate with other pathways that control PGC1α expression, remain unclear. BioEssays 25:538–541, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A clinical trial on mitochondrial replacement therapy is currently being conducted and if this technique proves effective, National Health Service England will fund MRT through the highly specialised services funding stream. This paper considers whether MRT should be publicly funded by the NHS. Given the current financial pressure the NHS is experiencing, a comprehensive discussion is essential. There is yet to be a thorough discussion on MRT funding, perhaps because this is a small-scale issue and presumed to be covered (...) by the HSS budget. However, the source of funding has not been confirmed due to the trial’s incompletion. Upon its completion, reasoned decisions need to be made over the allocation of scarce NHS resources. It is therefore important to consider the following arguments in advance. Three arguments given against NHS funding of MRT will be evaluated. The first argument against NHS funding examines the HSS overspending its budget in an underfunded NHS, suggesting funding must be carefully reprioritised. Second, the ethical issue of allowing public access to a technique with insufficient evidence behind it will be explored. The final point considers the option of privately funding MRT and how this would affect the treatment’s development. After illustrating the weaknesses of such arguments, it will be concluded that MRT should be funded by the NHS. (shrink)

In 2015 the UK became the first country in the world to legalise mitochondrial donation, a controversial germ line reproductive technology to prevent the transmission of mitochondrial disease. Dimond and Stephens track the intense period of scientific and ethical review, public consultation and parliamentary debates preceeding the decision. They draw on stakeholder accounts and public documents to explore how patients, professionals, institutions and publics mobilised within ‘for’ and ‘against’ clusters, engaging in extensive promissory, emotional, bureaucratic, ethical, embodied and (...) clinical labour to justify competing visions of an ethical future. They describe how this decision is the latest iteration of a UK sociotechnical imaginary in which the further liberalization of human embryo research and use is rendered legitimate and ethical through modes of consultation and permissive but strictly regulated licensing. Overall, this book presents a timely, multi-dimensional, and sociological account of a globally significant landmark in the history of human genetics, and will be relevant to those with an interest in genetics, Science, Technology and Society, the sociology of medicine, reproductive technology, and public policy debate. (shrink)

In 2015 the United Kingdom (UK) became the first nation to legalize egg and zygotic nuclear transfer procedures using mitochondrial replacement techniques (MRTs) to prevent the maternal transmission of serious mitochondrial DNA diseases to offspring. These techniques are a form of human germline genetic modification and can happen intentionally if female embryos are selected during the MRT clinical process, either through sperm selection or preimplantation genetic diagnosis (PGD). In the same year, an MRT was performed by a United (...) States (U.S.)-based physician team. This experiment involved a cross-border effort: the MRT procedure per se was carried out in the US, and the embryo transfer in Mexico. The authors examine the ethics of MRTs from the standpoint of genetic relatedness and gender implications, in places that lack adequate laws and regulation regarding assisted reproduction. Then, we briefly examine whether MRTs can be justified as a reproductive option in the US and Mexico, after reassessing their legalization in the UK. We contend that morally inadequate and ineffective regulations regarding egg donation, PGD, and germline genetic modifications jeopardize the ethical acceptability of the implementation of MRTs, suggesting that MRTs are currently difficult to justify in the US and Mexico. In addition to relevant regulation, the initiation and appropriate use of MRTs in a country require a child-centered follow-up policy and more evidence for its safety. (shrink)