Mitochondrial fragmentation in neurodegeneration

Abstract

Mitochondria are dynamic organelles that undergo continuous cycles of fission and fusion. These dynamic processes allow mitochondria to communicate, migrate and adapt to changing energy demands and cellular conditions. A group of large GTPases mediate mitochondrial fission and fusion. Important players in mammalian cells include mitofusin 1 and 2 (MFN1 and MFN2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (DRP1). Mutations in the mitochondrial fission and fusion GTPases MFN2, OPA1 and DRP1 cause neurodegenerative diseases. MFN2 mutations cause Charcot-Marie-Tooth subtype 2A (CMT2A) and sensory neuropathy type VI (HMSN VI), OPA1 mutations cause autosomal dominant optic atrophy (ADOA), and a DRP1 mutation caused a lethal defect in a human infant. Several triggers, including oxidative stress and altered regulation by cell-cycle kinases, contribute to the cell-specific shift in the balance between fission and fusion that is characteristic of sporadic neurodegenerative diseases. The emerging roles of mitochondrial fission and fusion, including synaptic maintenance, bioenergetics and genetic drift of mitochondrial DNA subpopulations, along with an increased appreciation of differences in the mitochondrial proteome in different cell types, might help to explain some of the unique characteristics of sporadic neurodegenerative diseases, such as their late onset and slow progression. Transcriptional regulation of mitochondrial biogenesis, exercise and reactive oxygen species management are three potential ways of reversing deleterious changes in mitochondrial dynamics.