Doug Wallace is a pioneer of the mitochondrial genome. I first met him at Stanford in the late 1970s and tried several times to entice him to speak at the Univ of Cincinnati in the 1990s and 2000s (never happened, he was always too much in demand; Doug is an excellent speaker and a great writer, as one can see from his attached review). As we all know, almost all cells of animals contain a nucleus and cytoplasm. The nucleus contains our nuclear DNA (nDNA; genome) on chromosomes. The cytoplasm contains many different subcellular components, perhaps the most important of which are mitochondria (considered the “powerhouse of the cell” because it generates most of our energy). Often overlooked is the mitochondrial genome — with its own set of genes, which of course are also subject to single-nucleotide variants (SNVs) and deleterious mutations, leading to diseases.
The worldwide incidence of type-2 diabetes, obesity, and autism (‘complex diseases’) is rising, and age-related diseases such as Alzheimer disease, Parkinson disease, and cancer are increasing as the population ages. Large amounts of money, time and effort are being spent, in an attempt to understand and treat these diseases, but have met with limited success to date. Perhaps some of the difficulty lies in the assumptions that organ-associated symptoms are the result of organ-specific defects, and that those clinically relevant genes exist only in nDNA. It is becoming increasingly realized that organ-specific symptoms can result from systemic mitochondrial bioenergetic defects — and some of the most important mitochondrial genes are involved. Doug Wallace has been beating this drum for more than three decades.
The eukaryotic cell (i.e. containing pairs of chromosomes) arose during evolution via amalgamation of two separate life forms: an archaeon (group of microorganisms that resemble bacteria but are different from them in their genetic makeup and certain aspects of cell structure) that gave rise to the nucleus and cytosol — and an α-proteobacterium (major phylum of gram-negative bacteria — which include a wide variety of pathogens, such as Escherichia, Salmonella, Vibrio, Helicobacter, Yersinia, Legionellales and many other notable genera) that gave rise to the mitochondrion. Over 2.5 billion years of eukaryotic-cell evolution, the nucleus became specialized in encoding the anatomical elements of the cell, whereas the mitochondrion became specialized in encoding the core energy elements.
The nDNA encompasses ~20,000 anatomical genes, which include the structural proteins for the mitochondrion and enzymes for mtochondrial DNA (mtDNA) maintenance and expression. The mtDNA contains only 13 polypeptide genes, but they are present in hundreds to thousands of copies per cell (whereas the nDNA comprises one-half the genes from each parent, the mtDNA almost always comes from the female). The mtDNA polypeptides are central electron- and proton-transport proteins for the mitochondrial energy-generating process, oxidative phosphorylation (OXPHOS); mtDNA can be thought of as “the wiring diagram of the mitochondrial power plant.” OXPHOS generates ~90% of the body’s energy by oxidizing hydrogen atoms from food with the oxygen breathed in, thus generating water, via the electron-transport chain (NADH–complex I (or succinate complex II)–coenzyme Q–complex III–cytochrome c–complex IV–oxygen). The energy — released as electrons, traverses complexes I, III, and IV — and is used to pump protons out across the mitochondrial inner membrane, thereby generating an electrochemical gradient that acts as a capacitor. The potential energy of this capacitor can drive complex V (ATP synthase) to condense ADP and inorganic phosphate, thereby forming ATP used for energy.
Specifically, maternally inherited mtDNA contains 37 critical bioenergetic genes, present in hundreds of copies per cell, but the ‘mitochondrial genome’ encompasses an additional 1,000–2,000 nDNA mitochondrial genes; the interaction between these two mitochondrial genetic systems provides explanations — for phenomena such as the non-Mendelian transmission of common complex diseases, age-related disease risk and progression, variable penetrance and expressivity, and gene–environment interactions (gee, where have I heard this term before?). Therrefore, mtDNA genetics contributes to the quantitative and environmental components of human genetics that cannot be explained by Mendelian genetics. Because mtDNA is maternally inherited and cytoplasmic, it clinically has fostered the first germline gene therapy, nuclear transplantation. However, effective interventions are still lacking for existing patients with mitochondrial dysfunction. These GEITP pages believe that more attention should be made to the ‘mitochondrial genome’. 🙂
Nat Genet Dec 2o18; 50: 1642–1649