Ultrastructural mitochondrial abnormalities in patients with sporadic amyotrophic lateral sclerosis.

A large number of neurodegenerative diseases are caused by impairment of mitochondrial function. Mutations in genes that encode proteins responsible for the shape and dynamics of mitochondria have been associated with some genetic neurodegenerative diseases, which implies that mitochondrial shape plays an important role in the health of neurons and muscle. Neurons are highly dependent on mitochondria because they have high energy demands and are unable to switch to glycolysis when mitochondrial oxidative phosphorylation is impaired. An ultrastructural hallmark of the synapse is the abundance of mitochondria, which are essential to maintaining calcium homeostasis and adequate levels of adenosine triphosphate (critical for nerve transmission). Neurons have extraordinarily long cellular processes, and tight control of mitochondrial dynamics facilitates the distribution of active mitochondria to dendrites and axon terminals. Higgins et al described vacuolated mitochondria in the early phases of motor neuron degeneration in transgenic mice with familial amyotrophic lateral sclerosis (ALS) and the SOD1 gene; they found that mutant SOD1 extends the outer mitochondrial membrane and expands the intermembrane space. Much less is known about the involvement of mitochondria in muscle of patients with ALS. Defects of the mitochondrial respiratory chain have been described in several patients with ALS. Comi and colleagues described a patient with early-onset and rapidly progressive motor neuron disease who harbored a heteroplasmic microdeletion of the mitochondrial DNA (mtDNA)– encoded subunit I of cytochrome-c oxidase (COX). Finsterer described a mother and 2 daughters with symptoms compatible with ALS. All 3 patients showed COXnegative muscle fibers, ultrastructurally abnormal mitochondria, and no mutations in SOD1, but they all harbored 3 mtDNA mutations, one in the transfer RNA gene, one in the cytochrome b gene, and one in the adenosine triphosphatase 6 gene. Recently, we reviewed the muscle biopsy specimens from 50 patients with typical sporadic ALS. Histochemical data showed variably severe COX deficiency in 23 of the 50 patients (46%). Of these 23 patients, 7 (30%) showed severe deficiency ( 10 COX-negative fibers of 100), and in these 7 patients, the biochemical defect of respiratory chain enzymes paralleled the histochemical defect.