TDP-43 stabilises the processing intermediates of mitochondrial transcripts

Abstract

The 43-kDa trans-activating response region DNA-binding protein 43 (TDP-43) is a product of a causative gene for amyotrophic lateral sclerosis (ALS). Despite of accumulating evidence that mitochondrial dysfunction underlies the pathogenesis of TDP-43–related ALS, the roles of wild-type TDP-43 in mitochondria are unknown. Here, we show that the small TDP-43 population present in mitochondria binds directly to a subset of mitochondrial tRNAs and precursor RNA encoded in L-strand mtDNA. Upregulated expression of TDP-43 stabilised the processing intermediates of mitochondrial polycistronic transcripts and their products including the components of electron transport and 16S mt-rRNA, similar to the phenotype observed in cells deficient for mitochondrial RNase P. Conversely, TDP-43 deficiency reduced the population of processing intermediates and impaired mitochondrial function. We propose that TDP-43 has a novel role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts.

Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases

“…In the cortical neurons of transgenic mice, the mitochondrial association of mutant TDP-43 was stronger than the endogenous protein in nontransgenic littermates, suggesting that mutant TDP-43 has a higher tropism for mitochondria. A recent study has also proposed that WT TDP43 may serve a physiological function by stabilizing a subset of tRNAs and mRNA intermediates in mitochondria ( Izumikawa et al, 2017 ). However, unlike the studies mentioned above, in human fibroblasts harboring mutant TDP-43, a decrease in mitochondria membrane potential was detected in the absence of alterations in oxygen consumption and mitochondrial localization of TDP-43 ( Onesto et al, 2016 ).…”

Abnormal RNA stability in amyotrophic lateral sclerosis

“…Similar changes in mitochondrial morphology and function are reported in models of ALS 39 , inclusion body myositis 51 , and Parkinson’s disease 52 . TDP-43 binds to and regulates the processing of transcripts encoding mitochondrial proteins 53 , 54 , and TDP-43 also contains a mitochondrial localizing sequence, leading to mitochondrial dysfunction upon cytoplasmic TDP-43 mislocalization 53 . Our results further emphasize mitochondrial abnormalities in ALS patient-derived cells, and highlight the deleterious effects of TDP-43 deposition on the metabolism of RNAs essential for oxidative phosphorylation.…”

TDP-43: From Alzheimer’s Disease to Limbic-Predominant Age-Related TDP-43 Encephalopathy

“…They provide energy and also participate in nearly all types of cell death, including apoptosis and necrosis, and contribute to a number of important physiological functions (Kroemer et al, 1998). Studies have shown that TDP-43 plays an important role in stabilizing mitochondrial function, and pathological TDP-43 can cause mitochondrial dysfunction (Izumikawa et al, 2017). Abnormal TDP-43 may cause mitochondrial dysfunction by affecting mitochondrial morphology, reactive oxygen species (ROS) generation, oxidative respiratory chain and localization.…”