Mitochondrial dynamics in cell death and neurodegeneration

Abstract

Mitochondria are highly dynamic organelles that continuously undergo two opposite processes, fission and fusion. Mitochondrial dynamics influence not only mitochondrial morphology, but also mitochondrial biogenesis, mitochondrial distribution within the cell, cell bioenergetics, and cell injury or death. Drp1 mediates mitochondrial fission, whereas Mfn1/2 and Opa1 control mitochondrial fusion. Neurons require large amounts of energy to carry out their highly specialized functions. Thus, mitochondrial dysfunction is a prominent feature in a variety of neurodegenerative diseases. Mutations of Mfn2 and Opa1 lead to neuropathies such as Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. Moreover, both Aβ peptide and mutant huntingtin protein induce mitochondrial fragmentation and neuronal cell death. In addition, mutants of Parkinson's disease-related genes also show abnormal mitochondrial morphology. This review highlights our current understanding of abnormal mitochondrial dynamics relevant to neuronal synaptic loss and cell death in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease.

Fig. 1

Schematic structure of the domains of proteins involved in mitochondrial dynamics. The length and topology of amino acids for each region are shown. All proteins have a GTPase domain found in dynamin-related proteins for hydrolysis of GTP. Drp1 and Opa1 have a GED domain (green). Transmembrane domains (orange) are found in Mfn1/2 and Opa1, and a mitochondrial localization signal sequence in the N-terminus is found in Opa1. Coiled-coil domains are found in fusion proteins (red). MLS mitochondrial localization signal, HR heptad repeat domain, CC coiled-coil domain, TM transmembrane domain)

Fig. 2

Proposed model of amyloid-β peptide (Aβ)-induced mitochondrial fission in Alzheimer’s disease. Aβ oligomers may interact with ABAD protein in mitochondria to generate ROS, inducing synaptic and neuronal injury. Aβ oligomers may also increase neuronal nitric oxide (NO) production by both NMDA receptor-dependent and -independent mechanisms. NO produces S-nitrosylation of Drp1 (forming SNO-Drp1). SNO-Drp1 contributes to synaptic and neuronal injury by leading to excessive mitochondrial fission and bioenergetic impairment