Mitochondrial and cellular model of aging. The upper line of cells diagrams the mitochondrial role in the energetic life and death of a cell. The bottom diagram represents the loss of cells in a tissue over the life of an individual through mitochondrial-mediated death, black cells. The minimum number of cells for the tissue to function normally is indicated by the dashed line.

Model of pancreatic β cell showing the mitochondrial regulation of insulin secretion. The light green blob associated with VDAC represents glucokinase. The green double squares in the plasma membrane on the left side represent the glucose transporter. The two pairs of double squares on the right side plasma membrane represent: below and labeled K_ATP the ATP gated K⁺ channel and above and labeled VDCa⁺⁺ the voltage-dependent Ca⁺⁺ channel. The circles with the internal “I” represent insulin containing vesicles. Other abbreviations as in Figure 2. Reprinted from Reference 25.

Human mitochondrial DNA map showing representative pathogenic and adaptive base substitution mutations. D-loop = control region (CR). Letters around the outside perimeter indicate cognate amino acids of the tRNA genes. Other gene symbols are defined in the text. Arrows followed by continental names and associated letters on the inside of the circle indicate the position of defining polymorphisms of selected region-specific mtDNA lineages. Arrows associated with abbreviations followed by numbers around the outside of the circle indicate representative pathogenic mutations, the number being the nucleotide position of the mutation. Abbreviations: DEAF, deafness; MELAS, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; LHON, Leber hereditary optic neuropathy; ADPD, Alzheimer and Parkinson disease; MERRF, myoclonic epilepsy and ragged red fiber disease; NARP, neurogenic muscle weakness, ataxia, retinitis pigmentosum; LDYS, LHON + dystonia; PC, prostate cancer.

Model for the proposed role for mitochondrial dysfunction in an energy-utilization tissue cell in metabolic and degenerative diseases, aging, and cancer. The mitochondrial pathophysiology of these clinical entities is envisioned to result from the interplay between mitochondrial energy production, ROS generation, and the initiation of apoptosis through activation of the mtPTP. These components of energy metabolism are modulated by environmental constraints such as caloric availability and cold stress through the regulation of the FOXO and PGC-1α transcription factors and the SIRT1 NAD⁺-dependent deacetylase. The FOXO transcription factors coordinately regulate mitochondrial energy metabolism through PGC-1α as well as the antioxidant and stress response genes necessary to cope with the increased oxidative stress of oxidative metabolism. SIRT1 fine-tunes the interrelationship between energy metabolism and apoptosis through the deacetylation of PGC-1α, p53, and the histone proteins. Caloric overload or inhibition of OXPHOS perturbs the cellular mitochondrial energetic balance resulting in increased ROS. The increased ROS and decreased mitochondrial energy output sensitizes the mtPTP, ultimately driving the cell to apoptotic death. The increased ROS also diffuses into the nucleus as H₂O₂ where it can mutate and activate proto-oncogenes (initiation) and can interact with NFκB, APE-1 and various kinases to initiate cell division (promotion) leading to neoplastic transformation (cancer). Figure abbreviations are PARP, poly ADP-ribose polymerase; SIRT1, the mammalian homologue to Sir2; FOXO3, the most ubiquitous mammalian forkhead transcription factor; P, a phosphorylated protein; Ac, an acetylated protein; IL, insulin ligand; ILL, insulin-like ligand; IR, insulin receptor; ILR, insulin-like growth factor receptor; IRE, insulin response element; PI3K, the PI3 kinase; PI2, the membrane-bound phosphotidyl-inositol diphosphate; PI3, membrane-bound phosphatidyl-inositol triphosphate, AKT 1/2, the AKT kinases; ATPsynβ, ATP synthase β subunit; cytc, cytochrome c.

Diagram outlining the migratory history of the human mtDNA haplogroups. Homo sapiens mtDNAs arose in Africa about 150,000 to 200,000 years before present (YBP), with the first African-specific haplogroup branch being L0, followed by the appearance in Africa of lineages L1, L2, and L3. In northeastern Africa, L3 gave rise to two new lineages, M and N. Only M and N mtDNAs succeeded in leaving Africa and colonizing all of Eurasia about 65,000 YBP. In Europe, N gave rise to the H, I, J, Uk, T, U, V, W, and X haplogroups. In Asia, M and N gave rise to a diverse range of mtDNA lineages including A, B, and F from N and C, D, and G from M. A, C, and D became enriched in northeastern Siberia and crossed the Bering land bridge about 20,000 to 30,000 YBP to found the Paleo-Indians. At 15,000 YBP, haplogroup X came to central Canada either from across the frozen Atlantic or by an Asian route of which there are no clear remnants today. At 12,000 to 15,000 YBP, haplogroup B entered the Americas, bypassing Siberia and the arctic, likely by moving along the Beringian Coast. Next at 7000 to 9000 YBP, a migration bringing a modified haplogroup A moved from the northeastern Siberia into northwestern North America to found the Na-Dene (Athebaskins, Dogrib, Apaches, and Navajos). Finally, relatively recently, derivatives of A and D moved along the Arctic Circle to found the Eskimos. These observations revealed two major latitudinal discontinuities in mtDNA variation: one between the Africa L haplogroups and the Eurasia and N and M derivatives and the other between the plethora of Central Asian mtDNA lineages and the almost exclusive presence of lineages A, C, and D northeastern Siberia, the latter spawning the Native American migrations. Since these discontinuities correspond to the transitions from tropical and subtropical to temperate and from temperate to arctic, we have proposed that these discontinuities were the result of climatic selection of specific mtDNA mutations that permitted certain female lineages to prosper in the increasingly colder northern latitudes. Reprinted from http://www.mitomap.org.

Diagram showing the relationships of mitochondrial oxidative phosphorylation (OXPHOS) to (a) energy (ATP) production, (b) reactive oxygen species (ROS) production, and (c) initiation of apoptosis through the mitochondrial permeability transition pore (mtPTP). The OXPHOS complexes, designated I to V, are complex I (NADH: ubiquinone oxidoreductase) encompassing a FMN (flavin mononucleotide) and six Fe-S centers (designated with a cube); complex II (succinate: ubiquinone oxidoreductase) involving a FAD (flavin adenine dinucleotide), three Fe-S centers, and a cytochrome b; complex III (ubiquinol: cytochrome c oxidoreductase) encompassing cytochromes b, c1 and the Rieske Fe-S center; complex IV (cytochrome c oxidase) encompassing cytochromes a + a₃ and CuA and CuB; and complex V (H⁺-translocating ATP synthase). Pyruvate from glucose enters the mitochondria via pyruvate dehydrogenase (PDH), generating acetylCoA, which enters the TCA cycle by combining with oxaloacetate (OAA). Cis-aconitase converts citrate to isocitrate and contains a 4Fe-4S center. Lactate dehydrogenase (LDH) converts excess pyruvate plus NADH to lactate. Small molecules defuse through the outer membrane via the voltage-dependent anion channel (VDAC) or porin. The VDAC together with ANT, Bax, and the cyclophilin D (CD) protein are thought to come together at the mitochondrial inner and outer membrane contact points to create the mtPTP. The proapoptotic Bax of the mtPTP is thought to interact with the anti-apoptotic Bcl2 and the benzodiazepine receptor (BD). The opening of the mtPTP is associated with the release of several proapoptotic proteins. Cytochrome c (cytc) interacts with and activates cytosolic Apaf-1, which then binds to and activates procaspase-9. The activated caspase-9 then initiates the proteolytic degradation of cellular proteins. Apoptosis initiating factor (AIF) and endonuclease G (EndoG) have nuclear targeting peptides that are transported to the nucleus and degrade the chromosomal DNA. Modified from Reference (237).