Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing “quality control” and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.

Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model

“…Several pathways and organelles have been highlighted in NMJ integrity maintenance and ALS physiopathology and may support our observations. First, mitochondrial breakdown has been linked to oxidative stress and NMJ disruption ( Chung and Suh, 2002 ; Dupuis et al, 2009 ; Dobrowolny et al, 2018b ; Zhou et al, 2019 ; Belosludtseva et al, 2023 ). Another possible mode of action leading to NMJ instability in ALS could be a direct influence of the enzyme acetylcholinesterase (AChE).…”

Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis

“…As described above, mitochondrial dysfunction in ALS is a multifaceted phenomenon, and determining whether it is a cause or consequence of the disease remains a challenge. While the literature suggests that mitochondrial impairment is observed early in the disease process (e.g., [335][336][337]), pinpointing the exact initiating event is complicated by the heterogeneity of ALS cases [187,338,339].…”

Mitochondrial Permeability Transition, Cell Death and Neurodegeneration

“…Mitochondrial dysfunction, including that which is associated with mPTP opening, is considered to be one of the key causes of death in both motor neurons and muscle cells in ALS [84,85]. Such ALS-related pathological processes as excitotoxicity [86] with a reduced calcium buffering capacity of the cytosol and mitochondria [87], overproduction of ROS and ONOO- [88], nitration of proteins including CypD and ANT [89], ATP level decrease, disturbances in mitochondrial dynamics [90], mitochondrial swelling and vacuolization [91], appear as triggers and consequences of mPTP opening [92].…”