Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu–Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial “metabolic threshold”, which may appear pivotal in ALS pathogenesis.

Multiomics study ofCHCHD10S59L-related disease reveals energy metabolism downregulation: OXPHOS and β-oxidation deficiencies associated with lipids alterations

“…Circulating contents of cholesterol, triglycerides and fatty acids were also found to be strongly altered in male Chchd10 S59L/+ mice ( Table 1 ), those alterations are known to occur over the course of ALS reflecting the metabolic environment [25]. This study showed that CHCHD10 S59L mutation is related to ALS phenotype with some specific known plasma biomarkers which correlated with described pathomechanisms of ALS [26, 27].…”

Network Spreading and Local Biological Vulnerability in Amyotrophic Lateral Sclerosis

“…4a). These terms include ‘ATP metabolic process’ [114], ‘gluconeogenesis’, ‘mitochondrial calcium ion transport’ [69, 96], ‘glycolytic process’ [131], ‘glycosphingolipid metabolic process’ [19, 58], ‘mitophagy’ [41, 79, 122], ‘positive regulation of mitochondrial fission’ [6, 71], ‘mitochondrial matrix’ [125], ‘mitochondrial membrane’ [25, 125], ‘integral component of mitochondrial inner membrane’ [25], ‘integral component of mitochondrial outer membrane’ [25], ‘protein import into mitochondrial matrix’ [75, 76], ‘negative regulation of amino acid transport’, ‘branchedchain amino acid catabolic process’ [155], ‘peroxisome’ [43, 53], ‘peroxisomal matrix’ [43, 53], all of which point toward altered energy metabolism and mitochondrial dysfunction. Additionally, categories related to cells’ cytoskeletal structure, such as ‘actin filament-based movement’, ‘apical dendrite’ [50], ‘microtubule associated complex’ [50, 147], and ‘anchored component of membrane’ are also implicated in the disease, which point to the structural dysregulations happening in the cells causing axonal transport disturbance [77], impairment of information integration in cells [50], and impairing cell adhesion.…”

“…2 Hemodynamic similarity: Hemodynamic similarity, often referred to as functional connectivity, summarizes the similarity across brain regions in terms of the synchronization and similarity of their co-fluctuation in the BOLD signal. The data incorporated to build the connectome comes from 326 unrelated healthy participants (145 males; age: [22][23][24][25][26][27][28][29][30][31][32][33][34][35] in the Human Connectome Project (HCP-S900 release), scanned using a 3T Connectome Skyra scanner [136]. In this dataset, each participant has undergone four 15-minute resting-state functional MRI scans, each with a TR of 720 ms. Data is preprocessed using the HCP minimal preprocessing pipeline.…”

Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts

“…Furthermore, Combo upregulated expression of VCP , a protein whose loss of function causes fALS and other degenerative disorders (40). Combo increased the expression of several subunits of mitochondrial respiratory chain complexes, which could have beneficial effects on bioenergetic capacity, known to be impaired in both genetic and sporadic forms of ALS (82). We identified several genes connected to RNA pol II transcription strongly downregulated by Combo, including YBX1 and FXR1 .…”