- Mitochondrial Theory of Aging
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- Mitochondrial DNA: impacting central and peripheral nervous systems
- Mitochondria and Aging
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- Original Research ARTICLE
- Mitochondrial dynamics and inheritance during cell division, development and disease
Because of their high-energy metabolism, neurons are highly dependent on mitochondria, which generate cellular ATP through oxidative phosphorylation. The mitochondrial genome encodes for critical components of the oxidative phosphorylation pathway machinery, and therefore mutations in mitochondrial DNA mtDNA cause energy production defects that frequently have severe neurological manifestations.
Here, we review the principles of mitochondrial genetics and focus on prototypical mitochondrial diseases to illustrate how primary defects in mtDNA or secondary defects in mtDNA due to nuclear genome mutations can cause prominent neurological and multisystem features. In addition, we discuss the pathophysiological mechanisms underlying mitochondrial diseases, the cellular mechanisms that protect mitochondrial integrity, and the prospects for therapy.
Although all cells require ATP to maintain homeostasis, neurons have special metabolic needs. The latter process has been shown to be a particularly high consumer of synaptic ATP Rangaraju et al. Synaptic ATP generation is stimulated by electrical activity and is generated by both glycolysis and mitochondrial function Rangaraju et al.
Mitochondrial Theory of Aging
Fly mutants with defects in transport of axonal mitochondria show synaptic defects Guo et al. In humans, mitochondrial dysfunction is often associated with pathology affecting the central and peripheral nervous systems Schon and Przedborski, Mitochondria are the source of oxidative phosphorylation OXPHOS , a metabolic pathway that is critical for the efficient extraction of energy from food sources Scheffler, Its components are largely encoded by the nuclear genome, but a handful of subunits are encoded by the small mitochondrial genome mtDNA , a semiautonomous, circular and multi-copy DNA present within mitochondria Figure 1.
Beyond metabolism, mitochondria have important functions in iron-sulfur cluster assembly, intracellular calcium handling, reactive oxygen species signaling ROS , apoptosis, and innate immunity Scheffler, At the top is the non-coding D-loop white , also known as the control region. This region is involved in mtDNA replication and transcriptional initiation.
Classic examples of point mutations associated with prototypical mitochondrial encephalomyopathies are noted with asterisks. B Oxidative phosphorylation and mtDNA gene products. The five enzyme complexes constituting the OXPHOS machinery reside in the mitochondrial inner membrane and consist of components encoded by both the nuclear and mitochondrial genomes.
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They are translated in the matrix of the mitochondrion and inserted into the inner membrane via the oxidase assembly OXA machinery. Mitochondrial ribosomes have polypeptides encoded by the nuclear genome. These polypeptides assemble into large and small ribosomal subunits that form complexes with rRNAs encoded by the mtDNA. This review focuses on the function of the mitochondrial genome and how defects in this genome can lead to neurological disease. We first review the general principles of mitochondrial genetics and discuss how mtDNA mutations affect mitochondrial function.
Finally, we discuss the pathogenic mechanisms underlying mtDNA disease and the prospects for therapy. Throughout, we emphasize the impact of defective mtDNA on the central and peripheral nervous systems. The mammalian mtDNA genome is To generate these 13 mtDNA gene products, the mitochondrial genome has an additional 24 genes that support a dedicated translational system utilizing a slightly different genetic code.
The mtDNA genome in mammals is highly compact compared to the organization of the nuclear genome. The only significant noncoding segment is the control region that regulates transcription and replication.
Mitochondrial DNA: impacting central and peripheral nervous systems
As would be expected, mutations in mtDNA frequently cause respiratory chain dysfunction. Inherited diseases caused by mtDNA mutations are passed through the maternal lineage Schon et al.
This feature arises from the fact that almost all eukaryotes show uniparental inheritance of mtDNA, and in the case of mammals, it is the maternal mtDNA that is exclusively passed onto the offspring.
Exclusive maternal inheritance of mtDNA is facilitated by the large size of the egg in comparison to the sperm. However, there also appears to be active mechanisms to ensure removal of paternal mtDNA.
Mammalian mitochondria are ubiquitinated, and this mark has been suggested to target the organelles for degradation upon fertilization Sutovsky et al. In nematodes, paternal mitochondria are removed by autophagy Al Rawi et al. In fertilized mammalian eggs, some autophagy markers are associated with the paternal mitochondria Al Rawi et al.
However, a recent study has argued that autophagy is not involved in degradation of paternal mitochondria in mice Luo et al. Maternal transmission of mtDNA has two unusual features. First, the mtDNA population undergoes a bottleneck phenomenon during oogenesis, such that only a small population of mtDNA molecules, estimated to be approximately , are amplified and transmitted Jenuth et al.
This feature can lead to rapid segregation of mtDNA variants within a few generations. For example, a rare mtDNA haplotype in the mother can become predominant in one of her offspring Koehler et al. The molecular mechanism of the bottleneck is poorly understood and has been attributed to a numerical reduction in mtDNA molecules in the developing oocyte Cree et al.
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The latter mechanism is plausible because mtDNA replication is not synchronized with the cell cycle, allowing variation in the number of times a particular mtDNA genome is replicated. Thus, a subpopulation of mtDNA molecules may be expanded at the expense of others due to selective replication or selective degradation.
The second unusual feature of maternal transmission is the presence of a quality control mechanism, termed purifying selection, that removes oocytes with a significant load of severe mtDNA mutations. Mice carrying a severe frameshift mutation in the ND6 mtDNA gene show progressive loss of the mutation in each subsequent generation Fan et al. In another study, the presence of selection in the female germline was detected through statistical analysis of inherited mtDNA mutations Stewart et al.
Analysis of the maternal transmission of these mtDNA mutations revealed bias in the position of the mutations in the offspring.
In the mtDNA protein-coding regions, synonymous mutations were more common than non-synonymous ones. In particular, there was greater suppression of mutations in the first and second codon positions, compared to the third position. Taken together, these two studies strongly imply purifying selection in the female germline as a mechanism to limit the inheritance of pathogenic mutations Stewart et al.
The molecular basis of purifying selection is unclear but it appears that this mechanism can sense and eliminate oocytes with low levels of mtDNA mutations that normally do not result in respiratory chain defects, at least when such mtDNA mutations are studied in experimental cell culture systems. This phenomenon may explain why very severe mtDNA mutations, such as those involving large deletions, are rarely inherited.
Less severe mutations, such as point mutations affecting the tRNA genes, are commonly transmitted maternally. Such mutations may escape purifying selection because they must accumulate to very high levels before a respiratory chain defect is apparent, although more work is required to understand this effect. Sequence data from human populations indicate that the mitochondrial genome accumulates inherited mutations at a rate several orders of magnitude higher than that of nuclear DNA Pakendorf and Stoneking, The mitochondrial genome also shows a several-hundred fold increase in the spontaneous mutation rate compared to the nuclear genome Khrapko et al.
Low levels of mtDNA heteroplasmy the presence of more than one mtDNA haplotype within a cell can be detected by deep sequencing in virtually any individual. A portion of these heteroplasmic variants can be found in the mother and therefore appear to be maternally inherited.
The rest are presumed to be de novo mutations that accumulated in somatic tissues with age He et al. It has been estimated that one in every healthy newborn carries a common pathogenic mtDNA mutation at a level below clinical manifestation Elliott et al.
At a low frequency, such mutations, either inherited or de novo, will lead to disease if the mutation load rises to a sufficiently high level. Epidemiological studies estimate the prevalence of mtDNA disease as 1 in —10, Chinnery et al.
Original Research ARTICLE
Cells can tolerate a high load of mtDNA mutations before encountering bioenergetic failure. The understanding of the pathological effects of mtDNA mutations has been greatly facilitated by the development of cybrid technology. In this approach, host cells lacking mtDNA serve as the recipient of mitochondria from mutant cells King and Attardi, , thereby allowing the pathological effects of mtDNA variants to be studied in the context of a uniform nuclear background.
Cybrid cell models have been developed for numerous mtDNA mutations associated with mitochondrial encephalomyopathies Chomyn et al. Studies in mice also support this idea. Cells therefore have a high threshold for mtDNA mutations, with the threshold dependent on the exact nature of the mutation.
As a result, patients with mtDNA disease have a mosaic distribution of respiratory chain deficiency. In skeletal muscle, for example, histochemical analysis may reveal a patchy distribution of OXPHOS-negative fibers intermingling with functionally normal fibers Figure 2A and B.
These features arise from the high-copy number of mtDNA and the need to accumulate mtDNA mutations to high levels before cellular dysfunction is evident.
Images are courtesy of Dr. Maria Lucia Valentino. In affected cells, the mutational load is generally quite high and often homoplasmic. These observations have led to the idea that inherited mtDNA mutations undergo random genetic drift during cell division mitotic segregation , such that some cell lineages eventually acquire mutational loads that surpass the threshold for bioenergetic failure DiMauro and Schon, Because of the variables of inherited mutational load, mosaicism, and genetic drift, even the same mtDNA mutation can lead to different clinical outcomes in affected individuals.
Mitochondrial dynamics and inheritance during cell division, development and disease
Post-mitotic tissues such as skeletal muscle, cardiac muscle, brain and peripheral nerves are the most frequently affected by mtDNA pathogenic mutations, due to their high energy requirements DiMauro et al. In addition to this bioenergetic effect, some mutations may also have secondary effects on apoptosis or ROS production. Mice with extensive mtDNA mutations Kujoth et al.
In considering the function of mtDNA and the effects of mtDNA mutations, it is important to note that the mitochondria within a cell are dynamic and continually engage in fusion and fission division Chan, In mitochondrial fusion, two mitochondria merge into a single, larger organelle.
Because mitochondria have double membranes, fusion involves the sequential fusion of the outer and inner membranes, and separate machinery have been identified for these processes Figure 3A. Outer membrane fusion requires mitofusin GTPases Mfn1 and Mfn2 located in the mitochondrial outer membrane. Mitochondrial fusion is balanced by the opposing process of mitochondrial fission, which requires yet another GTPase, dynamin-related protein 1 Drp1.
These dynamic processes are essential for proper mitochondrial function and serve to homogenize the mitochondrial population. A Molecules involved in mitochondrial fusion.
Mitochondria are dynamic organelles that continually undergo fusion and fission. The balance of these opposing actions controls mitochondrial morphology and enables mixing of the mitochondrial population. Because mitochondria have 2 membranes, mitochondrial fusion is a multi-step process. Outer membrane OM fusion requires the mitofusins 1 and 2 green , transmembrane GTP hydrolyzing enzymes.
B Nuclearly encoded genes important for mtDNA replication and maintenance. Mgme1 mitochondrial genome maintenance exonuclease 1 cleaves single-stranded DNA and is essential for mtDNA maintenance. Several additional proteins, listed at the bottom, are important for regulating dNTP pools or levels in the mitochondria and are important for mtDNA maintenance see Table I.
Mitochondrial encephalomyopathies are a group of diseases due to a defect in mitochondrial function, and they often have central and peripheral nervous system involvement Schon et al. KSS is sporadic, and the latter three diseases are maternally inherited. In , there were breakthrough descriptions of the molecular defects responsible for some of these clinical entities. Single mtDNA macrodeletions were associated mitochondrial myopathies Holt et al.
These findings established that mtDNA mutations cause both maternally inherited and sporadic mitochondrial disease.