Progressive Mitochondrial SOD1G93A Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.

Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis

“…Intriguingly, CMT2A and DOA sometimes overlap [ 91 , 93 , 94 , 95 ], suggesting that the consequences of a primary impairment in mitochondrial fusion from whatever genetic cause preferentially damage peripheral and retinal neurons. There are varied reports of decreased MFN and OPA1 expression in ALS [ 78 , 96 , 97 , 98 ]. Accordingly, Wang et al employed a genetic approach to enhance neuronal mitofusin activity in the murine SOD1 G93A mouse [ 97 ].…”

Forty years of the adrenal chromaffin cell through ISCCB meetings around the world

“…The SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS) has also been explored. In Hamburg, ultrastructural alterations and function of mitochondria (Antonio García) and CGs (Fernando Padín) in CCs from SOD1 G93A mice were reported [ 123 ]. Of note is a report on altered mitochondrial metabolism and reduced secretion in CCs from the TS2-neo mouse model of autism [ 24 ].…”

Calcium Overload and Mitochondrial Metabolism

“…Mitochondrial ultrastructure undergoes dramatic changes during metabolic perturbations or in the presence of certain genetic modifications [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. As such, calcium overload is a way to induce mitochondrial structural modifications.…”