Mitochondrial DNA mutations in disease and aging

Abstract

The human mitochondrial genome involves over 1,000 genes, dispersed across the maternally inherited mitochondrial DNA (mtDNA) and the biparentally inherited nuclear DNA (nDNA). The mtDNA encodes 13 core proteins that determine the efficiency of the mitochondrial energy-generating system, oxidative phosphorylation (OXPHOS), plus the RNA genes for their translation within the mitochondrion. The mtDNA has a very high mutation rate, which results in three classes of clinically relevant mtDNA mutations: recently deleterious germline line mutations resulting in mitochondrial disease; ancient regional variants, a subset of which permitted humans to adapt to differences in their energetic environments; and somatic mutations that accumulate with age eroding mitochondrial energy production and providing the aging clock. Mutations in nDNA-encoded OXPHOS structural genes can also cause mitochondrial disease, and alterations in nDNA mitochondrial biogenesis genes can destabilize the mtDNA and lead to clinical phenotypes. Finally, when combined, nonpathogenic nDNA and mtDNA protein variants can be functionally incompatible and cause disease. The essential functions of the conserved mtDNA proteins and their high mutation rate raise the question as to why the cumulative mtDNA genetic load does not result in species extinction. Studies of mice harboring deleterious mtDNA mutations have shown that the mammalian ovary selectively eliminates the most deleterious mtDNA mutations. However, milder mtDNA mutations are transmitted through the ovary and the female germline and introduced into the general population. This unique genetic system provides a flexible method for generating genetic variation in cellular and organismal energetics that permits species to adapt to alterations in their regional energetic environment.

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

“…However, cells contain hundreds of mitochondria, and for a long time, the general opinion was that removal of damaged mitochondria via mitophagy also contributes to a constant removal of mutant mtDNA [3]. This view has now radically changed, because it became clear that mtDNA mutations are at the core of many human diseases such as Leber's hereditary optic neuroretinopathy (LHON), myoclonic epilepsy associated with ragged-red fibres (MERRF), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), Kearns -Sayre Syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) [4,5]. Even though wild-type mtDNA molecules are still present in disease cells (a situation referred to as heteroplasmy 1 ), mutant mtDNA molecules with point mutations, partial deletions or duplications are present at such high heteroplasmy levels per cell that they cause pathological phenotypes.…”

Assessing the Delivery of Molecules to the Mitochondrial Matrix Using Click Chemistry

“…Among the many bioactive molecules we seek to target to mitochondria are those that interact with mitochondrial DNA (mtDNA); as this is essential for mitochondrial function,9 mutations to mtDNA cause a number of diseases 10. Considerable efforts are ongoing to develop molecules that alter mtDNA function in a sequence specific way, either as probes or as potential therapies 2.…”

A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle

“…Complex IV is comprised of three subunits encoded by mitochondrial DNA and 10 subunits encoded by nuclear DNA 4 . In addition to mutations in mitochondrial DNA-encoded COX genes 5,6 , mutations in nuclear DNA-encoded COX component genes and COX accessory factors cause COX deficiency [6][7][8] . For example, SURF1 is responsible for Leigh syndrome 9,10 , SCO1 for neonatal-onset hepatic failure and encephalopathy 11 , SCO2 for fatal infantile cardioencephalomyopathy 12 , and COX15 for fatal hypertrophic cardiomyopathy 13 .…”