Mitochondrial dynamics General concepts and clinical implications

ADOA= : autosomal dominant optic atrophy; ATP= : adenosine triphosphate; CMT= : Charcot-Marie-Tooth disease; DLP1= : dynamin-like protein 1; DLP1= : dynamin-like protein 1 gene; DRP1= : dynamin-related protein 1; DRP1= : dynamin-related protein 1 gene; EGR2= : early growth response 2 gene; EOP= : early-onset Parkinson disease; GDAP1= : ganglioside-induced differentiation-associated protein 1; GDAP1= : ganglioside-induced differentiation-associated protein 1 gene; GST= : glutathione-S-transferase; HAP1= : huntingtin-associated protein; LHON= : Leber hereditary optic neuropathy; MFF= : mitochondrial fission factor; MFN= : mitofusin; MFN2= : mitofusin 2 gene; MIEF= : mitochondrial elongation factor; mtDNA= : mitochondrial DNA; OPA1= : optic atrophy type 1 gene; PARK2= : parkin gene; PARL= : presenilin-associated rhomboid-like protein; PINK1= : PTEN-induced putative kinase protein-1; PINK1= : PTEN-induced kinase 1 gene; PD= : Parkinson disease Mitochondria have an essential role in adenosine triphosphate (ATP) production by oxidative phosphorylation, β oxidation of fatty acids, biosynthesis of amino acids and steroids; they also regulate calcium (Ca2+) homeostasis, and, indirectly, participate in apoptotic cell death. Mitochondria are highly dynamic organelles. Their shape is controlled by fusion and fission, their internal structure changes in response to their physiologic state, and they participate in reciprocal interactions with other organelles, including the endoplasmic reticulum. Mitochondria are actively transported both anterograde and retrograde along the cytoskeleton to reach specific subcellular locations according to the local energy requirements. There is a quality control mechanism by which dysfunctional mitochondria are removed by mitophagy. Defects in mitochondrial dynamics, including fusion, fission, transport, and mitophagy, are features of several neurodegenerative diseases. Autosomal dominant axonal Charcot-Marie-Tooth type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA) are associated with mutations in mitochondrial fusion proteins, whereas autosomal recessive CMT has been linked to mutations of a protein that participates in mitochondrial fission. Neurodegenerative disorders such as Parkinson disease (PD) are associated with disruption of mitochondrial dynamics at multiple levels, such as disruption of proper mitophagy. Mutations in proteins involved in mitophagy, such as Parkin and PTEN-induced kinase 1 (PINK1), have been linked to autosomal recessive PD. The mechanisms underlying mitochondrial fusion, fission, trafficking, and quality control and their clinical implications have been the subject of several reviews.1,–,4 Mitochondrial fusion and fission control the length, shape, size, and number of mitochondria; these processes maintain the overall morphology and functional properties of the mitochondrial population. At steady state, there is a balance between mitochondrial fusion and fission and the balance is regulated by different types of dynamin-like protein guanosine triphosphate (GTP)ases (figure 1).1,4 Figure 1 Mitochondrial fusion and fission Mitochondrial fusion depends on members of the mitofusin …