The Cellular Mitochondrial Genome Landscape in Disease

Mutations of almost every mtDNA-encoded gene have been implicated in enhanced reactive oxygen species (ROS) production and disease. The spatiotemporal distribution of somatic mtDNA mutations within an individual is determined by their inheritance, formation, intercellular transfer, propagation, and removal over time. Diversity in the distribution and relative levels of mtDNA mutations (heteroplasmy) may contribute to varying rates of progression of aging and disease between cells of an individual. MtDNA heteroplasmy is modulated by stochastic and deterministic processes, including through the action of conserved homeostatic cellular mechanisms, such as fission/fusion, mitophagy, and the mitochondrial unfolded protein response. Mitochondrial genome (mitochondrial DNA, mtDNA) lesions that unbalance bioenergetic and oxidative outputs are an important cause of human disease. A major impediment in our understanding of the pathophysiology of mitochondrial disorders is the complexity with which mtDNA mutations are spatiotemporally distributed and managed within individual cells, tissues, and organs. Unlike the comparatively static nuclear genome, accumulating evidence highlights the variability, dynamism, and modifiability of the mtDNA nucleotide sequence between individual cells over time. In this review, we summarize and discuss the impact of mtDNA defects on disease within the context of a mosaic and shifting mutational landscape. Mitochondrial genome (mitochondrial DNA, mtDNA) lesions that unbalance bioenergetic and oxidative outputs are an important cause of human disease. A major impediment in our understanding of the pathophysiology of mitochondrial disorders is the complexity with which mtDNA mutations are spatiotemporally distributed and managed within individual cells, tissues, and organs. Unlike the comparatively static nuclear genome, accumulating evidence highlights the variability, dynamism, and modifiability of the mtDNA nucleotide sequence between individual cells over time. In this review, we summarize and discuss the impact of mtDNA defects on disease within the context of a mosaic and shifting mutational landscape. cellular hybrids that contain nuclear DNA (nDNA) and mtDNA of different origin. Isolated mitochondria of a certain genotype are introduced into recipient cells fully or partially depleted of their own mtDNA to investigate the effect of specific mtDNA mutations against different backgrounds of nDNA and at different heteroplasmy levels. illness caused by mutations in the mtDNA that affect mitochondrial functionality. Mosaic levels of heteroplasmy, together with other factors, influence the progression and pathology of mitochondrial diseases. Disease nomenclature is eponymic or descriptive, often accounting for the most common symptoms of a given disease. Deleterious mtDNA lesions need to cross a threshold of abundance before clinical symptoms present. This threshold varies depending on the nature of the mtDNA mutation as well as the environment, tissue type, and underlying genetic profile of the individual. For common mitochondrial diseases, such as MERRF and MELAS, estimates range between 60% and 95% heteroplasmy [161Nadee N. Moraes C.T. Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease.FEBS Lett. 2018; 592: 728-742Crossref PubMed Scopus (12) Google Scholar, 162Nonaka I. Mitochondrial diseases.Curr. Opin. Neurol. Neurosurg. 1992; 5: 622-632PubMed Google Scholar, 163Shokolenko I.N. et al.Aging: a mitochondrial DNA perspective, critical analysis and an update.World J. Exp. Med. 2014; 4: 46-57Crossref PubMed Google Scholar]. a remnant of the mitochondrial endosymbiont. In animals, mtDNA structure is well conserved as a single circular, double-stranded DNA molecule that is 10–20 kb in size [164Kolesnikov A.A. Gerasimov E.S. Diversity of mitochondrial genome organization.Biochemistry (Mosc). 2012; 77: 1424-1435Crossref PubMed Scopus (14) Google Scholar] (see also Box 1 in the main text). With few exceptions, mtDNA inheritance is almost exclusively maternal. cellular reaction to mitochondrial dysfunction that modulates transcription levels of a multitude of genes to ensure cellular survival. UPRmt does not attenuate heteroplasmy levels, but rather increases the tolerance of mtDNA damage. the oxidative phosphorylation of ADP into ATP following the transfer of electrons from NADH or FADH2 to O2 through the electron transport chain (complexes I–IV). The energy released from these redox reactions is stored as a pH gradient and an electrical potential across the mitochondrial inner membrane, which is used by ATP synthase (complex V). nuclear-encoded exclusive mtDNA polymerase, which in humans, comprises two subunits: POLG exerting polymerase and proofreading activity, and the accessory subunit POLG2, which increases processivity. Polymerase γ is assisted by the helicase TWINKLE, and the mitochondrial single strand-binding protein mtSSB. Perturbations of the mtDNA replication machinery induce numerous mtDNA mutations that resemble the accumulation of mtDNA damage during aging. often quantified with fluorescent reporters of mitochondrial superoxide (MitoSOX red dye) and cellular H2O2 (dichlorofluorescein acetate, DCFDA; Amplex Red). The products of redox reactions of ROS with macromolecules, such as lipids, proteins, or DNA, also serve as indicators for increased oxidative stress. enzymes implicated in the processing and neutralization of ROS or ROS precursors: They include superoxide dismutases (SOD1 and SOD2), as well as catalases and glutathione peroxidase. ROS can also be buffered by molecules such as vitamin C or E; however, if the capacity of the scavenging systems is exceeded, cellular damage may occur.