Mitochondrial DNA damage as driver of cellular outcomes

Abstract

Mitochondria are primarily involved in energy production through the process of oxidative phosphorylation (OXPHOS). Increasing evidence has shown that mitochondrial function impacts a plethora of different cellular activities, including metabolism, epigenetics, and innate immunity. Like the nucleus, mitochondria own their genetic material, but this organellar genome is circular, present in multiple copies, and maternally inherited. The mitochondrial DNA (mtDNA) encodes 37 genes that are solely involved in OXPHOS. Maintenance of mtDNA, through replication and repair, requires the import of nuclear DNA-encoded proteins. Thus, mitochondria completely rely on the nucleus to prevent mitochondrial genetic alterations. As most cells contain hundreds to thousands of mitochondria, it follows that the shear number of organelles allows for the buffering of dysfunction—at least to some extent—before tissue homeostasis becomes impaired. Only red blood cells lack mitochondria entirely. Impaired mitochondrial function is a hallmark of aging and is involved in a number of different disorders, including neurodegenerative diseases, diabetes, cancer, and autoimmunity. Although alterations in mitochondrial processes unrelated to OXPHOS, such as fusion and fission, contribute to aging and disease, maintenance of mtDNA integrity is critical for proper organellar function. Here, we focus on how mtDNA damage contributes to cellular dysfunction and health outcomes.