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23.1D: The Evolution of Mitochondria - Biology

23.1D: The Evolution of Mitochondria - Biology


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Mitochondria are energy-producing organelles that are thought to have once been a type of free-living alpha-proteobacterium.

Learning Objectives

  • Explain the relationship between endosymbiosis and mitochondria to the evolution of eukaryotes

Key Points

  • Eukaryotic cells contain varying amounts of mitochondria, depending on the cells’ energy needs.
  • Mitochondria have many features that suggest they were formerly independent organisms, including their own DNA, cell-independent division, and physical characteristics similar to alpha-proteobacteria.
  • Some mitochondrial genes transferred to the nuclear genome over time, yet mitochondria retained some genetic material for reasons not completely understood.
  • The hypothesized transfer of genes from mitochondria to the host cell’s nucleus likely explains why mitochondria are not able to survive outside the host cell.

Key Terms

  • crista: cristae (singular crista) are the internal compartments formed by the inner membrane of a mitochondrion
  • vacuole: a large, membrane-bound, fluid-filled compartment in a cell’s cytoplasm
  • endosymbiosis: when one symbiotic species is taken inside the cytoplasm of another symbiotic species and both become endosymbiotic

Relationship between Endosymbiosis and Mitochondria

One of the major features distinguishing prokaryotes from eukaryotes is the presence of mitochondria. Eukaryotic cells contain anywhere from one to several thousand mitochondria, depending on the cell’s level of energy consumption. Each mitochondrion measures between 1 to 10 µm in length and exists in the cell as an organelle that can be ovoid to worm-shaped to intricately branched. Mitochondria arise from the division of existing mitochondria. They may fuse together. They move around inside the cell by interactions with the cytoskeleton. However, mitochondria cannot survive outside the cell. As the amount of oxygen increased in the atmosphere billions of years ago and as successful aerobic prokaryotes evolved, evidence suggests that an ancestral cell with some membrane compartmentalization engulfed a free-living aerobic prokaryote, specifically an alpha-proteobacterium, thereby giving the host cell the ability to use oxygen to release energy stored in nutrients. Alpha-proteobacteria are a large group of bacteria that includes species symbiotic with plants, disease organisms that can infect humans via ticks, and many free-living species that use light for energy. Several lines of evidence support the derivation of mitochondria from this endosymbiotic event. Most mitochondria are shaped like alpha-proteobacteria and are surrounded by two membranes, which would result when one membrane-bound organism engulfs another into a vacuole. The mitochondrial inner membrane involves substantial infoldings called cristae that resemble the textured, outer surface of alpha-proteobacteria. The matrix and inner membrane are rich with enzymes necessary for aerobic respiration.

Mitochondria divide independently by a process that resembles binary fission in prokaryotes. Specifically, mitochondria are not formed de novo by the eukaryotic cell; they reproduce within the cell and are distributed between two cells when cells divide. Therefore, although these organelles are highly integrated into the eukaryotic cell, they still reproduce as if they are independent organisms within the cell. However, their reproduction is synchronized with the activity and division of the cell. Mitochondria have their own circular DNA chromosome that is stabilized by attachments to the inner membrane and carries genes similar to genes expressed by alpha-proteobacteria. Mitochondria also have special ribosomes and transfer RNAs that resemble these components in prokaryotes. These features all support that mitochondria were once free-living prokaryotes.

Mitochondrial Genes

Mitochondria that carry out aerobic respiration have their own genomes, with genes similar to those in alpha-proteobacteria. However, many of the genes for respiratory proteins are located in the nucleus. When these genes are compared to those of other organisms, they appear to be of alpha-proteobacterial origin. Additionally, in some eukaryotic groups, such genes are found in the mitochondria, whereas in other groups, they are found in the nucleus. This has been interpreted as evidence that genes have been transferred from the endosymbiont chromosome to the host genome. This loss of genes by the endosymbiont is probably one explanation why mitochondria cannot live without a host.

Despite the transfer of genes between mitochondria and the nucleus, mitochondria retain much of their own independent genetic material. One possible explanation for mitochondria retaining control over some genes is that it may be difficult to transport hydrophobic proteins across the mitochondrial membrane as well as ensure that they are shipped to the correct location, which suggests that these proteins must be produced within the mitochondria. Another possible explanation is that there are differences in codon usage between the nucleus and mitochondria, making it difficult to be able to fully transfer the genes. A third possible explanation is that mitochondria need to produce their own genetic material so as to ensure metabolic control in eukaryotic cells, which indicates that mtDNA directly influences the respiratory chain and the reduction/oxidation processes of the mitochondria.


Mitochondrial evolution

Viewed through the lens of the genome it contains, the mitochondrion is of unquestioned bacterial ancestry, originating from within the bacterial phylum α-Proteobacteria (Alphaproteobacteria). Accordingly, the endosymbiont hypothesis--the idea that the mitochondrion evolved from a bacterial progenitor via symbiosis within an essentially eukaryotic host cell--has assumed the status of a theory. Yet mitochondrial genome evolution has taken radically different pathways in diverse eukaryotic lineages, and the organelle itself is increasingly viewed as a genetic and functional mosaic, with the bulk of the mitochondrial proteome having an evolutionary origin outside Alphaproteobacteria. New data continue to reshape our views regarding mitochondrial evolution, particularly raising the question of whether the mitochondrion originated after the eukaryotic cell arose, as assumed in the classical endosymbiont hypothesis, or whether this organelle had its beginning at the same time as the cell containing it.


1 Answer 1

This is one of the most intriguing questions of eukaryotic evolution. As far as I know and have read, the autogenous theory is not accepted. There are quite some reviews on this topic. Also there is a wonderful book by Nick Lane on mitochondria called Power Sex and Suicide. You would be interested to read it.

There are no sufficient evidences for the evolutionary transition from prokaryotes to eukaryotes which somewhat suggests that this was some kind of quantum jump. For example:

  • There are no microfossil records for the evolutionary intermediates
  • Almost all eukaryotic features including organelles, syngamy, nucleus etc emerged simultaneously

So to answer how it exactly happened is quite difficult.

As for the autogenous theory it would have been impossible for the huge eukaryotic cell (the precursor of mitochondria) to meet its energy demands without an organelle like mitochondria i.e. a prokaryote as large as a eukayotic cell wouldn't survive. You may check this post.

There are eukaryotic cells that lack mitochondria (eg. Entamoeba histolytica ) or have one with reduced functionality. However, these are not intermediates in evolution but have lost the functionality in a retrograde manner.

There is one more evidence to support the endosymbiosis theory: There is this observation that organelles that are less numerous in a cell have retained more of their genome compared to those with the organelles that are surplus numbers (eg. plastids vs mitochondria). This is called the Limited Transfer Window Hypothesis which reasons that the organelle to nuclear gene translocation would have happened because of organellar injury and the likelihood of a cell tolerating one is higher if there are more number of organelles.

This article suggests an alternative view that predatory bacteria like Bdellovibrio could have settled in a prokaryotic host. There are other cases of bacterial endosymbiont in a larger bacteria (I need some time to mine up the reference. Read it a while back) but these are not the the ancestors of eukaryotes.


Author Summary

Mammalian germ cells (eggs and sperm) are immortal in the sense that they propagate successive generations. In contrast, somatic (body) cells do not persist to the next generation. Yet neither plants nor basal animals such as sponges and corals have a germline they simply form gametes from stem cells in adult tissues. The reasons for these differences are unknown. We develop an evolutionary model showing that the germline evolved in response to selection on mitochondria, the powerhouses of cells. Mitochondria retain their own genes, which occur in multiple copies per cell. In plants and basal animals, the mitochondrial genes mutate slowly. Segregation over the many rounds of cell division to form an adult generates variation in mutant mitochondria between gametes, sufficient for natural selection to improve mitochondrial function. In more active animals from the Cambrian explosion onwards, the mitochondrial mutation rate rose strongly. This required the evolution of a dedicated germline, set aside early in development, with lowered mutational input. It also favoured large eggs (starting with thousands of mitochondria) and culling, following overproduction (atresia). Both devices maintain mitochondrial quality. The evolution of germline sequestration had profound consequences, allowing the emergence of complex developmental processes and truly disposable adult tissues.

Citation: Radzvilavicius AL, Hadjivasiliou Z, Pomiankowski A, Lane N (2016) Selection for Mitochondrial Quality Drives Evolution of the Germline. PLoS Biol 14(12): e2000410. https://doi.org/10.1371/journal.pbio.2000410

Academic Editor: Thomas Kirkwood, Newcastle University, United Kingdom

Received: June 23, 2016 Accepted: November 29, 2016 Published: December 20, 2016

Copyright: © 2016 Radzvilavicius et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The model was implemented in GitHub and can be accessed at: https://github.com/ArunasRadzvilavicius/GermlineEvolution All underlying data files are available at: https://github.com/ArunasRadzvilavicius/GermlineEvolution/tree/master/FigureData.

Funding: EPSRC https://www.epsrc.ac.uk/ (grant number EP/L504889/1). Received by ZH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NERC http://www.nerc.ac.uk/ (grant number NE/G00563X/1). Received by AP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EPSRC https://www.epsrc.ac.uk/ (grant number EP/F500351/1, EP/I017909/1, EP/K038656/1). Received by AP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Leverhulme Turst https://www.leverhulme.ac.uk/ (grant number RPG-425). Received by NL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EPSRC https://www.epsrc.ac.uk/ (EP/F500351/1). Received by AR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ROS, reactive oxygen species UV, ultraviolet


Affiliations

Department of Biology, University of Padua, Padua, Italy

Marta Giacomello, Aswin Pyakurel, Christina Glytsou & Luca Scorrano

Veneto Institute of Molecular Medicine, Padua, Italy

Aswin Pyakurel, Christina Glytsou & Luca Scorrano

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

Contributions

M.G. and L.S. conceptualized, wrote most of and edited the article. A.P. and C.G. wrote subsections. All authors approved the final content.

Corresponding author


Sexually antagonistic evolution of mitochondrial and nuclear linkage

Arunas Radzvilavicius, Department of Mathematics, University of Bergen, Bergen, Norway.

Iain G. Johnston, Computational Biology Unit, University of Bergen, Bergen, Norway.

School of Biological Sciences, Monash University, Melbourne, Vic., Australia

School of Biological Sciences, Monash University, Melbourne, Vic., Australia

School of Biological Sciences, Monash University, Melbourne, Vic., Australia

Department of Mathematics, University of Bergen, Bergen, Norway

Computational Biology Unit, University of Bergen, Bergen, Norway

Arunas Radzvilavicius, Department of Mathematics, University of Bergen, Bergen, Norway.

Iain G. Johnston, Computational Biology Unit, University of Bergen, Bergen, Norway.

Department of Mathematics, University of Bergen, Bergen, Norway

Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia

Arunas Radzvilavicius, Department of Mathematics, University of Bergen, Bergen, Norway.

Iain G. Johnston, Computational Biology Unit, University of Bergen, Bergen, Norway.

School of Biological Sciences, Monash University, Melbourne, Vic., Australia

School of Biological Sciences, Monash University, Melbourne, Vic., Australia

School of Biological Sciences, Monash University, Melbourne, Vic., Australia

Department of Mathematics, University of Bergen, Bergen, Norway

Computational Biology Unit, University of Bergen, Bergen, Norway

Arunas Radzvilavicius, Department of Mathematics, University of Bergen, Bergen, Norway.

Iain G. Johnston, Computational Biology Unit, University of Bergen, Bergen, Norway.

Abstract

Across eukaryotes, genes encoding bioenergetic machinery are located in both mitochondrial and nuclear DNA, and incompatibilities between the two genomes can be devastating. Mitochondria are often inherited maternally, and theory predicts sex-specific fitness effects of mitochondrial mutational diversity. Yet how evolution acts on linkage patterns between mitochondrial and nuclear genomes is poorly understood. Using novel mito-nuclear population-genetic models, we show that the interplay between nuclear and mitochondrial genes maintains mitochondrial haplotype diversity within populations, and selects both for sex-independent segregation of mitochondrion-interacting genes and for paternal leakage. These effects of genetic linkage evolution can eliminate male-harming fitness effects of mtDNA mutational diversity. With maternal mitochondrial inheritance, females maintain a tight mitochondrial–nuclear match, but males accumulate mismatch mutations because of the weak statistical associations between the two genomic components. Sex-independent segregation of mitochondria-interacting loci improves the mito-nuclear match. In a sexually antagonistic evolutionary process, male nuclear alleles evolve to increase the rate of recombination, whereas females evolve to suppress it. Paternal leakage of mitochondria can evolve as an alternative mechanism to improve the mito-nuclear linkage. Our modelling framework provides an evolutionary explanation for the observed paucity of mitochondrion-interacting genes on mammalian sex chromosomes and for paternal leakage in protists, plants, fungi and some animals.


23.1D: The Evolution of Mitochondria - Biology

Endosymbiosis: Lynn Margulis

Margulis and others hypothesized that chloroplasts (bottom) evolved from cyanobacteria (top).

The Modern Synthesis established that over time, natural selection acting on mutations could generate new adaptations and new species. But did that mean that new lineages and adaptations only form by branching off of old ones and inheriting the genes of the old lineage? Some researchers answered no. Evolutionist Lynn Margulis showed that a major organizational event in the history of life probably involved the merging of two or more lineages through symbiosis.

Symbiotic microbes = eukaryote cells?
In the late 1960s Margulis (left) studied the structure of cells. Mitochondria, for example, are wriggly bodies that generate the energy required for metabolism. To Margulis, they looked remarkably like bacteria. She knew that scientists had been struck by the similarity ever since the discovery of mitochondria at the end of the 1800s. Some even suggested that mitochondria began from bacteria that lived in a permanent symbiosis within the cells of animals and plants. There were parallel examples in all plant cells. Algae and plant cells have a second set of bodies that they use to carry out photosynthesis. Known as chloroplasts, they capture incoming sunlight energy. The energy drives biochemical reactions including the combination of water and carbon dioxide to make organic matter. Chloroplasts, like mitochondria, bear a striking resemblance to bacteria. Scientists became convinced that chloroplasts (below right), like mitochondria, evolved from symbiotic bacteria — specifically, that they descended from cyanobacteria (above right), the light-harnessing small organisms that abound in oceans and fresh water.


Mitochondria are thought to have descended from close relatives of typhus-causing bacteria.

The genetic evidence
In the 1970s scientists developed new tools and methods for comparing genes from different species. Two teams of microbiologists — one headed by Carl Woese, and the other by W. Ford Doolittle at Dalhousie University in Nova Scotia — studied the genes inside chloroplasts of some species of algae. They found that the chloroplast genes bore little resemblance to the genes in the algae's nuclei. Chloroplast DNA, it turns out, was cyanobacterial DNA. The DNA in mitochondria, meanwhile, resembles that within a group of bacteria that includes the type of bacteria that causes typhus (see photos, right). Margulis has maintained that earlier symbioses helped to build nucleated cells. For example, spiral-shaped bacteria called spirochetes were incorporated into all organisms that divide by mitosis. Tails on cells such as sperm eventually resulted. Most researchers remain skeptical about this claim.


Origin of Mitochondria and Chloroplasts

This theory is based on the similarities of chloroplasts and mitochondria with prokaryotic cells. These organelles possess their own genetic material (DNA) as well as the machinery for protein synthesis. According to this theory, eukaryotic cells developed from primitive “proto-eukaryotic cells” which were anaerobic and utilized the glycolytic pathway for energy generation.

These proto-eukaryotic cells were large in size and were able to take nutrients into the cell from the outer environment through phagocytosis.

Mitochondria are proposed to have evolved from primitive prokaryotes that could utilize oxygen for respiration (aerobic prokaryotes) following their ingestion into the proto-eukaryotic cells through the process of phagocytosis (Fig. 20.8). The O2 utilizing prokaryotic cells became symbionts of the proto-eukaryotic cells which had ingested them.

It is envisaged that during evolution, these prokaryotic symbionts lost their unnecessary functions and evolved to become the present day mitochondria.

Today, some of the mitochondrial proteins are encoded by the cell nucleus and are synthesized in the cytoplasm on cytoplasmic ribosomes, while several others are encoded by the mtDNA and are synthesized within the mitochondria itself in association with the mitochondrial ribosomes.

Migration of DNA from mitochondria and chloroplasts into the nuclear DNA has been documented this kind of DNA is called promiscuous DNA. The existence of promiscuous DNA explains why nuclear genes code for some of the mitochondrial proteins and also suggests the manner in which nucleus may have acquired this capability it also supports the endosymbiont theory of origin of the organelles.

Chloroplasts are proposed to have evolved from the prokaryotes capable of photosynthesis (Fig. 20.8). These photosynthetic prokaryotes are thought to have been ingested by the proto-eukaryotic cells and in due course established symbiotic relationship with them.

During the evolution, they lost their unnecessary functions and developed into the present-day chloroplasts. It has been suggested that the chloroplasts of different plant species containing different chlorophyll pigments evolved from different symbiotic events.

For example, blue green algae containing chlorophyll a and phycobilins are believed to have become symbionts in the proto-eukaryotic cells which developed into red algae.

Similarly, hypothetical photosynthetic prokaryotes containing chlorophyll a and c (yellow prokaryotes) became symbionts in the proto-eukaryotic cells which ultimately evolved into brown algae, diatoms and dinoflagellates.

The yellow prokaryotes are now extinct. Another group of hypothetical photosynthetic prokaryotes containing chlorophylls a and b (green prokaryotes) were ingested by the proto-eukaryotic cells which later evolved into green algae and higher plants. The green prokaryotes have also become extinct.

The bases for the endosymbiont theory lie in the similarities of the organelles (chloroplasts and mitochondria) with prokaryotic cells and in their dissimilarities from the eukaryotic cells. The major points of these similarities and dissimilarities are summarized in Table 20.6.

2. Direct Filiation Theory:

According to this theory, the chloroplasts and mitochondria did not evolve from prokaryotic cells ingested from outside but they are believed to have developed within the primitive “proto-eukaryotic cells”. It is proposed that cytoplasmic vesicles were formed by the invagination of the plasma membranes of the proto-eukaryotic cells.

These cytoplasmic vesicles also enclosed some genetic material (DNA) and gradually evolved into the present day organelles. For the evolution of mitochondria and chloroplasts, three models have been proposed.

(1) Model of Raff and Mahler:

In the proto-eukaryotic cell, plasma membrane contained the respiratory mechanisms of electron transfer and oxidative phosphorylation. The plasma membrane invaginated to produce free cytoplasmic vesicles which enclosed the respiratory path­ways. Later it acquired plasmid or extra-chromosomal fragments of DNA.

This DNA contained genes for tRNA, rRNA and mRNA coding for the hydrophobic proteins of the respiratory membrane.

(2) Model of Cavalier-Smith:

This is a general model that suggests the origin of mitochondria, chloroplasts, nucleus, Golgi complex and lysosomes etc. According to this model, budding off and fusion of plasma membrane (a process of endocytosis) enclosed some extra chromo­somal DNA segment (or plasmid).

Some of these structures developed to become mitochondria, while some others developed to become chloroplasts a similar process is believed to be involved in the formation of nuclear membrane that enclosed the chromosomes to produce the nucleus.

(3) Model of Reijnders:

According to this model, DNA of the proto-eukaryotic cell duplicated and the two copies of the DNA were enclosed by separate membranes to make separate compartments. Much of the DNA of one compartment was eliminated leaving only that part which was necessary for mitochondrial function this compartment ultimately developed into mitochondria.

There was no loss of DNA from the other compartment and it finally developed into the nucleus. Evolution of chloroplasts is proposed to have occurred through a similar process.


Mitochondrial DNA in evolution and disease

Cellular organelles called mitochondria contain their own DNA. The discovery that variation in mitochondrial DNA alters physiology and lifespan in mice has implications for evolutionary biology and the origins of disease. See Letter p.561

The maternally inherited DNA found in cytoplasmic organelles called mitochondria encodes the central proteins involved in energy production — the main function of this organelle. Yet it has been assumed that the extraordinarily high sequence variability of mitochondrial DNA is of little consequence. On page 561, Latorre-Pellicer et al. 1 dispel this erroneous notion.

The authors transferred mitochondrial DNA (mtDNA) from a mouse strain called NZB to the nuclear DNA (nDNA) background of another strain, C57BL/6, and then compared C57BL/6 mice that harboured NZB or C57BL/6 mtDNA. The two mtDNA sequences differ in genetic variants that confer 12 amino-acid substitutions and 12 changes in RNA molecules involved in mitochondrial protein synthesis. Comparison of the mice throughout their lives revealed huge differences in mitochondrial function, insulin signalling, obesity and longevity. This and related studies 2,3 clearly demonstrate that naturally occurring mtDNA variation is not neutral, and that the interaction between mtDNA sequence variants and nDNA can have profound effects on mammalian biology.

Why should this be of general interest? It turns out that the amount of variation between NZB and C57BL/6 mtDNAs is about the same as that between two unrelated human mtDNAs, so mtDNA variation and its effect on nDNA gene expression is also relevant to people.

Mouse and human mtDNA sequences can evolve only by sequentially accumulating mutations along radiating maternal lineages. For humans, functional mutations arose as women migrated out of Africa to colonize the rest of the world, modifying their cellular energy metabolism and allowing our ancestors to adapt to new regional environmental challenges. The mtDNA types (haplotypes) that acquired these environmentally advantageous mutations became widespread in their respective environments to give rise to regional groups of related haplotypes, called haplogroups. This regional selection explains why, of all the mtDNA lineages that evolved in Africa over the first 100,000 years of human history, only two mtDNAs (dubbed M and N) successfully left Africa 65,000 years ago to colonize the rest of the world. It also explains why only N mtDNAs colonized Europe, whereas both M and N colonized Asia, and why only five mtDNAs colonized the Americas (reviewed in ref. 4). Because human mtDNA diversity evolved from a single mtDNA, functional mtDNA variation that allows regional population isolation may also contribute to speciation 4 . Hence, mtDNA haplogroups are fundamental to the biology of both mice and men.

Because mitochondria have a bioenergetic role, it makes sense that mtDNA variation affects our physiology and our ability to adapt to environmental change. Variation in mtDNA genes can permit accommodation to new diets or adjustment to thermal stress and activity demands, and can even alter the regulation of cell death 4 . The correlation between human or mouse mtDNA variation and a broad range of traits, including longevity, physical capacity and, in humans, predisposition to a wide spectrum of metabolic and degenerative diseases and forms of cancer 4,5 , confirms the functional importance of mtDNA variation.

Nuclear gene expression is also affected by mtDNA variation, owing to the role of the mitochondrial energy-production system in modulating the levels of high-energy molecules generated through mitochondrial metabolism. High-energy mitochondrial metabolic products, such as the molecules ATP, acetylCoA and α-ketoglutarate, drive the modification of cytoplasmic signalling proteins and also add molecular modifications to nuclear proteins, which, together with nDNA modifications, constitute the epigenome. Changes in cellular signalling and the epigenome regulate nDNA gene expression. This coupling between the mitochondrion and the nucleus is crucial because no cellular function can proceed without sufficient energy. The nucleus must 'know' that mitochondria can generate the required energy before proceeding with DNA replication and transcription, for example.

Studying cells that have the same nucleus but different levels of a pathogenic mtDNA mutation — a change in an RNA molecule in which nucleotide 3243 is guanine (3243G) instead of the normal adenine — has helped to define the nature of mtDNA–nDNA interactions. Each cell contains hundreds of mtDNA copies, so both mutant and normal mtDNAs can be present in the cell in different proportions, a state known as heteroplasmy. When the 3243G mutation is present at a frequency of 10–30%, patients can manifest diabetes or, in rare cases, autism at 50–90%, the mutation manifests as neurological, heart and muscle problems and at 100%, it can result in childhood disease and death. A study 6 of nuclear gene expression in cell lines containing different percentages of the 3243G mutation revealed that each of these clinical classes of heteroplasmy is associated with a distinct nuclear gene-expression profile. In humans, then, as in Latorre-Pellicer and colleagues' mice, subtle changes in mitochondrial function resulting from mtDNA variation can have profound effects on nuclear gene expression, cellular physiology and individual health.

Uniparental inheritance of mtDNA is almost universal among animals, and mtDNA lineages are functionally different, so it might be predicted that artificially mixing two different mtDNA haplotypes in the same cell could be deleterious. Consistent with this prediction, mixing NZB mtDNAs with mtDNAs from a strain called 129 (whose mtDNA is similar to that of C57BL/6) in C57BL/6 mice results in mice that are hypo-active, hyper-excitable and have severe long-term-memory defects 7 . Hence, biparental inheritance of different mtDNAs can be deleterious, and the NZB and 129–C57BL/6 mtDNAs are functionally different.

Because mtDNA haplogroup variation has been shaped by environmental selection, it follows that mitochondria might be key sensors of environmental changes. Thanks to our growing understanding of the many regulatory roles of mitochondria, a holistic picture of cell biology has started to emerge (Fig. 1). In this scenario, changes in the environment would affect mitochondrial bioenergetics and alter the production of high-energy mitochondrial molecules. Altered concentrations of these mitochondrial molecules drive the chemical modification of cytoplasmic-signalling and epigenomic proteins, reprogramming nDNA gene expression. The altered nDNA gene-expression status then feeds back to modify mitochondrial gene expression and re-establish energetic homeostasis and health. However, if the local environmental changes are too severe to be managed by an individual's mtDNA-haplogroup-defined physiological state, or if recent deleterious mtDNA mutations are too pathogenic, this feedback homeostasis system may fail, resulting in progressive energetic decline, disease and ultimately death.

Latorre-Pellicer et al. 1 report that the transfer of mitochondrial DNA (mtDNA) from one mouse strain to another has pronounced effects on biology, demonstrating that mitochondrial genetic variation is not neutral and that mitochondrial–nuclear interactions are of central importance to mammalian physiology. Mitochondrial function is directly influenced by environmental changes, so the mitochondrion must have a central role in mediating between environmental perturbations and genomic responses. High-energy molecules produced by mitochondria modify the cytoplasmic signalling proteins and 'epigenomic' proteins that regulate nuclear DNA (nDNA) expression. These changes reprogram gene expression, altering expression of nDNA- and mtDNA-derived proteins that act in and on the mitochondria — these alterations feed back on mitochondrial function. If energetic homeostasis can be re-established, health and longevity are preserved. However, if genetic or environmental changes are too extreme, energy production declines, leading to disease and even death.

Latorre-Pellicer and colleagues' study provides direct evidence that naturally occurring mtDNA variation is fundamental to an individual's characteristics and health. This information supports a model whereby mitochondrial physiological states determined by mtDNA variation sense environmental perturbations and send the appropriate signals to the nucleus to produce the optimal gene-expression response. Footnote 1


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Keywords: arginylation, arginyltransferase, mitochondria, biogenesis, respiration, respiratory chain complexes

Citation: Jiang C, Moorthy BT, Patel DM, Kumar A, Morgan WM, Alfonso B, Huang J, Lampidis TJ, Isom DG, Barrientos A, Fontanesi F and Zhang F (2020) Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1. Front. Cell Dev. Biol. 8:603688. doi: 10.3389/fcell.2020.603688

Received: 07 September 2020 Accepted: 23 November 2020
Published: 21 December 2020.

Cesare Indiveri, University of Calabria, Italy

Brijesh Kumar Singh, Duke-NUS Medical School, Singapore
Steven Michael Claypool, Johns Hopkins University, United States

Copyright © 2020 Jiang, Moorthy, Patel, Kumar, Morgan, Alfonso, Huang, Lampidis, Isom, Barrientos, Fontanesi and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

† Present address: Chunhua Jiang, Pharmacology Center, Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., China Shijiazhuang Pharmaceutical Company, Shijiazhuang, China
Devang M. Patel, Department of Diabetes, Monash University, Melbourne, VIC, Australia
Akhilesh Kumar, Department of Botany, Banaras Hindu University, Varanasi, India



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