Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. In order to address the question of a putative role of mitochondrial dysfunction in the pathogenesis of ALS, we studied the mitochondrial DNA (mtDNA) and mitochondrial respiratory chain enzyme activities in spinal cords of ALS patients and in control subjects without neuropathologic abnormalities. Using a Ôdouble PCR and digestionÕ technique to estimate the levels of randomly distributed point mutations in two small regions of the mtDNA, we found significantly higher levels of mutant mtDNA in the spinal cord of ALS patients compared to controls. No large-scale rearrangements were found, but the amount of mtDNA, measured by Southern blot, was significantly lower in the ALS samples. This reduction correlated well with a decrease of citrate synthase (CS) activity, a mitochondrial marker, as were the activities of respiratory chain complexes I + III, II + III, and IV, suggesting a loss of mitochondria in ALS spinal cords.

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

“…In addition, high power microscopy evidenced damage to cristae, edema and altered membrane continuity. These findings are in consonance with mitochondrial abnormalities reported in the central nervous system of SALS patients and animal models of motor neuron degeneration 8,10 . Our present investigation suggests that changes taking place in skin mitochondria may reflect to some extent the mitochondrial abnormalities of the degenerating nervous system.…”

“…Afifi and colleagues 6 first reported abnormal mitochondrial morphology in the atrophic muscles of SALS patients and, subsequently, mitochondrial abnormalities have been reported in the central nervous system [7][8][9][10] , liver cells 11 and peripheral blood lymphocytes 12 of SALS patients. Muscle biopsies in SALS have shown increased mitochondrial volume associated to increased calcium levels 13 ; also, reduced activity of mitochondrial respiratory chain complex I and complex IV in skeletal muscle and the spinal cord have been reported 14,15 .…”

“…Interestingly, conglomerates of dark mitochondria at the presynaptic terminals of anterior spinal motor neurons were described by Sasaki and colleagues 28 , suggesting mitochondrial involvement in disabled synaptic contacts between lower motor neurons and their inputs. In addition, functional abnormalities of the mitochondria were described in the CNS, liver and muscle of SALS patients 10,11,14 . These changes suggest that the neurochemical basis for the observed morphological changes are widespread among different tissues and may consist in impaired mitochondrial bioenergetics, loss of membrane potential, reduced calcium buffering capacity and disrupted calcium homeostasis 29 .…”

Sirt1/PGC-1

“…SOD1 présente une localisation cytosolique mais également mitochondriale [2] et, de façon inté-ressante, les patients atteints de la forme sporadique présentent des anomalies morphologiques au niveau des mitochondries des axones proximaux et de la moelle épinière [3]. Un déficit d'activité des complexes I et IV de la chaîne respiratoire mitochondriale a également été rapporté [4]. Il n'est pas encore possible d'établir avec certitude si les anomalies mitochondriales sont la cause ou la conséquence de la dégénérescence des [5].…”

Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model

“…Massive mitochondrial degeneration is also observed in motor neurons of G93A SOD1 mutant mice at the onset of the disease (8), when electron transfer chain activity and ATP synthesis appear severely injured (9). Furthermore, a selective decrease in the activity of cytochrome c oxidase, encoded by the mitochondrial genome, occurs in motor neurons of sporadic ALS patients (10), and the reduction in the amount of mitochondrial DNA in the spinal cord of ALS patients correlates with a decrease in the activities of citrate synthase and the respiratory chain complexes IϩIII, IIϩIII, and IV (11).…”