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

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.

Keywords: amyotrophic lateral sclerosis; mitochondria-targeted therapies; mitochondrial dysfunction; motor neuron degeneration; neurodegeneration; pathological mechanisms; therapeutic interventions.

Figure 1

Overview of mitochondrial functions. Mitochondrial bioenergetics is driven by the oxidation of different substrates and is stimulated by calcium. Flux of electrons through the electron transport chain creates a transmembrane proton gradient of about 160 mV in the resting state, which fuels Adenosine Triphosphate (ATP) synthesis in the mitochondrial matrix. Leakage of electrons in some bioenergetic reactions generates reactive oxygen species (ROS) that are involved in important cellular signaling processes. Abbreviations: ADP: Adenosine Diphosphate; CI: Complex I; CII: Complex II; CIII: Complex III; CIV: Complex IV; Cyt c: Cytochrome c; ETF: Electron Transfer Flavoprotein; FAD: Flavin Adenine Dinucleotide; IMM: Inner Mitochondrial Membrane; MCU: Mitochondrial Calcium Uniporter; MPC: Mitochondrial Pyruvate Carrier; ΔΨ_m: Mitochondrial Transmembrane Electrochemical Potential; NAD: β-Nicotinamide adenine dinucleotide; NADH: β-Nicotinamide adenine dinucleotide 2′-phosphate reduced form.

Figure 2

Dysregulated mitochondrial trafficking in ALS Models. Anomalies in mitochondrial trafficking are a prevalent phenomenon across various ALS models. Notably, both anterograde and retrograde transport processes are compromised in this context. Intriguingly, emerging research suggests a temporal sequence in which retrograde transport disruption precedes anterograde transport impairment. Dysfunction in retrograde transport is intimately associated with mitophagy deficits, resulting in the inefficient removal of dysfunctional mitochondria in TDP 43 ALS mutant mice. Conversely, cortical neurons from the E18 embryos of ALS SOD1 mutant rats exhibit alterations in anterograde transport linked to a reduction in Miro expression, ultimately leading to mitochondrial transport stagnation. These perturbations in both transport pathways culminate in abnormal mitochondrial clustering, diminished Ca²⁺ buffering capacity, and compromised ATP production. In extreme cases, these abnormalities can trigger axonal stress, ultimately contributing to cell death and neurodegeneration.

Figure 3

Mitochondria-targeted therapies for ALS featuring (A) metabolic enhancers, (B) antioxidants, and (C) anti-apoptotic agents. Abbreviations: AcCoA: acetyl coenzyme A; CK: Creatine kinase; ETC: electron transport chain; FAO: fatty acid beta-oxidation; mPTP: mitochondrial permeability transition pore; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PDP, pyruvate dehydrogenase phosphatase; ROS: reactive oxygen species; RNS: reactive nitrogen species; TCA: tricarboxylic acid cycle.