A Mitochondrial Paradigm for Metabolic and Degenerative Diseases, Aging, and Cancer

Abstract

The human cell is assembled from two different organisms: the nucleo‐cytosol organism which specializes in structure and whose genes are Mendelian and the mitochondrial organism which specializes in energy and whose genes are maternal and stochastic. Inherited pathogenic mitochondrial DNA (mtDNA) mutations have been linked to a wide range of metabolic and degenerative diseases and the introduction of mtDNA mutations into the mouse germline has demonstrated that mtDNA mutations are sufficient to cause age‐related diseases. Somatic mtDNA mutations accumulate with age in a broad spectrum of organisms and introduction of catalase into the mouse mitochondrial matrix reduces the mtDNA somatic mutation rate and extends life span. Increasing Drosophila cAMP levels also reduces mitochondrial reactive oxygen species (ROS) and extends life span, and treating short‐lived Drosophila mutants with mitochondrially‐targeted antioxidants can restore the life span. Ancient adaptive mtDNA polymorphisms have been associated with altered risk for metabolic and neurodegenerative diseases and somatic mtDNA mutations are elevated in the brains of patients with neurodegenerative disease. Finally, both germline and somatic mtDNA mutations are associated with various cancers. Therefore, diseases which appear “complex” when viewed exclusively from the nucleo‐cytosol perspective might be more readily understood if the contribution of the mitochondrial organism were also considered.