Association between TDP-43 and mitochondria in inclusion body myositis

Abstract

Inclusion body myositis (IBM) is the most common cause of primary myopathy in individuals ages 50 years and over, and is pathologically characterized by protein aggregates of p62 and mislocalized cytoplasmic TDP-43 as well as mitochondrial abnormalities in affected muscle fibers. Our recent studies have shown the accumulation of TDP-43 in mitochondria in neurons from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), and revealed mitochondria as critical mediators of TDP-43 neurotoxicity. In this study, we investigated the association between mitochondria and TDP-43 in biopsied skeletal muscle samples from IBM patients. We found that IBM pathological markers TDP-43, phosphorylated TDP-43, and p62 all coexisted with intensively stained key subunits of mitochondrial oxidative phosphorylation complexes I-V in the same skeletal muscle fibers of patients with IBM. Further immunoblot analysis showed increased levels of TDP-43, truncated TDP-43, phosphorylated TDP-43, and p62, but decreased levels of key subunits of mitochondrial oxidative phosphorylation complexes I and III in IBM patients compared to aged matched control subjects. This is the first demonstration of the close association of TDP-43 accumulation with mitochondria in degenerating muscle fibers in IBM and this association may contribute to the development of mitochondrial dysfunction and pathological protein aggregates.

Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases

“…The most direct evidence is that the pathologically relevant TDP-43 has been repeatedly proven to exist inside or outside the mitochondria, and is functionally involved in the regulation of mitochondrial morphology, transport, and function [ 5 ]. In addition, mutant TDP-43 impairs the mitochondrial dynamics, and the overexpression of TDP-43 will cause abnormal aggregation and a loss of function of mitochondria, resulting in the progressive loss of neurons [ 27 – 29 ]. It is worth mentioning that inhibiting the mitochondrial localization of TDP-43 can block its toxicity [ 17 , 30 ], suggesting that the removal of abnormally aggregated TDP-43 and dysfunctional or damaged mitochondria, and blocking the interaction between TDP-43 and mitochondria may be an effective way to treat neurodegenerative diseases.…”

“…The binding of misfolded proteins to mitochondria can cause mitochondrial dysfunction, leading to the progressive degeneration of neurons. Previous studies have shown that the mutant TDP-43 damages the mitochondrial dynamics, which causes the abnormal aggregation and a loss of normal function of mitochondria, resulting in a progressive loss of neurons [ 27 – 29 ]. Moreover, recent evidence has shown that inhibiting the mitochondrial localization of TDP-43 can block the toxicity of TDP-43, suggesting that the removal of abnormally aggregated TDP-43 and dysfunctional or damaged mitochondria, and suppressing the TDP-43 interaction with mitochondria may be an effective way to treat neurodegenerative diseases [ 17 , 30 ].…”

“…The lack of mitochondria, excess ROS, or both, are likely to be the driving forces of aging, as they reduce the adaptability of cells, cause damage to other organelles, and cause mutations in the nuclear genome [ 25 , 26 ]. In addition, mutant TDP-43 can damage mitochondrial dynamics, and the overexpression of TDP-43 can cause abnormal aggregation of mitochondria and loss of their normal functions, leading to progressive loss of neurons [ 27 – 29 ]. Moreover, inhibiting the mitochondrial localization of TDP-43 can block the TDP-43-induced mitochondrial dysfunction [ 17 , 30 ], suggesting that the removal of abnormally aggregated TDP-43 and dysfunctional or damaged mitochondria and restoring the interaction of TDP-43 with mitochondria may be an effective way to treat neurodegenerative diseases.…”

Mitoautophagy: A Unique Self-Destructive Path Mitochondria of Upper Motor Neurons With TDP-43 Pathology Take, Very Early in ALS

“…For instance, mutant TDP-43 interaction with Mfn2 is reported to induce mitochondrial fragmentation (Davis et al, 2018). Studies in neuron-like cell lines, mutant TDP-43 inside the mitochondria was also shown to bind to mitochondria transcribed mRNA that encodes the subunits of the oxidative phosphorylation system and impaired their assembly and thus function (Salvatori et al, 2018; Huntley et al, 2019). Mutant TDP-43 is reported to disrupt the mitochondria-ER interactions, which are important sites of lipid transfer between the two organelles (Stoica et al, 2014).…”

Mitophagy and the Brain

“…This raises the possibility that mutant SOD1 may drive neurodegeneration by damaging mitochondria. TDP43 mutants are also observed within mitochondria and appear to induce mitochondrial dysfunction [228][229][230][231][232]. Both TDP43 and SOD1 are known to aggregate within motor neurons and muscle; TDP43 interacts with proteins critical to mitophagy in an inhibitory manner [205,230,231,[233][234][235][236][237].…”