Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Abstract

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant

“…Indeed, inhibition of TDP-43 mitochondrial localization has been shown to block its neuronal toxicity ( 95 ). Taken together, all these observations suggest that mitochondrial dysfunction could play an important role in TDP-43 proteinopathies, as recently reviewed in detail ( 96 ), and the results from our study add to this line of evidence. Another interesting aspect is that it might have been expected to observe opposite effects for the two opposite conditions: S375G (loss of phosphorylation) and S375E (constitutive phosphorylation).…”

Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

“…As it was mentioned, neuropathological hallmark of the disease in the vast majority of ALS patients are TDP-43 aggregates in the cytoplasm of motor neurons [ 7 ]. On the other hand, numerous missense mutations in gene TARDBP are provoking TDP-43 accumulation in mitochondria [ 57 ]. Possible crucial connection of TDP-43, mtDNA and inflammation in pathogenesis of ALS has been demonstrated recently in a remarkable study by Yu at al.…”

Icaritin protects SH-SY5Y cells transfected with TDP-43 by alleviating mitochondrial damage and oxidative stress

“…The interaction between TDP-43 and OXPHOS-related mt-mRNA affects the mitochondrial respiratory chain, resulting in a decrease in ATP production, a decrease in the MMP and an increase in ROS levels. This increase in ROS levels promotes the TDP-43/OXPHOS-related mt-mRNA interaction, forming a vicious cycle ( Lucini & Braun, 2021 ). Lipid peroxides produced by the body during oxidative stress leads to mitochondrial dysfunction by inhibiting the mitochondrial respiratory chain and enzyme activity, the extent of which can be reflected by the MDA content.…”