Nonmuscle myosin IIB regulates Parkin-mediated mitophagy associated with amyotrophic lateral sclerosis-linked TDP-43

Abstract

C-terminal fragments of Tar DNA-binding protein 43 (TDP-43) have been identified as the major pathological protein in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how they affect cellular toxicity and neurodegeneration, including the modulation process remains unknown. This study revealed that the C-terminal fragment of TDP-43 (TDP-25) was localized primarily to mitochondria and caused abnormal mitochondrial morphology, inducing Parkin-mediated mitophagy. Also, we discovered that the knockdown of selective autophagy receptors, such as TAX1BP, Optineurin, or NDP52 caused TDP-25 accumulation, indicating that TDP-25 was degraded by mitophagy. Interestingly, myosin IIB, a nonmuscle type of myosin and actin-based motor protein, is mostly colocalized to TDP-25 associated with abnormal mitochondria. In addition, myosin IIB inhibition by siRNA or blebbistatin induced mitochondrial accumulation of insoluble TDP-25 and Tom20, and reduced neuronal cell viability. Our results suggest a novel role of myosin IIB in mitochondrial degradation of toxic TDP-25. Therefore, we proposed that regulating myosin IIB activity might be a potential therapeutic target for neurodegenerative diseases associated with TDP-43 pathology.

Parkin beyond Parkinson’s Disease—A Functional Meaning of Parkin Downregulation in TDP-43 Proteinopathies

“…Apart from the above-mentioned direct regulation of PARK2 by TDP-43 ( Section 5 ), potentially affecting mitochondria, numerous observations of enhanced mitochondrial localization of TDP-43 (either entire protein or its C- and N-terminal fragments) point to a global mechanism how TDP-43 can interfere with proper mitochondrial function and specifically mitophagy, as reviewed in Reference [ 138 ]. Consistently, overexpression models of TDP-43 and its C-terminal fragments display enhanced mitophagy, including parkin-mediated mitophagy [ 141 , 142 ]. Interestingly, the degradation of the C-terminal fragment of TDP-43 (CTF TDP-25) itself, localizing in mitochondria, is mitophagy-dependent [ 142 ].…”

“…Consistently, overexpression models of TDP-43 and its C-terminal fragments display enhanced mitophagy, including parkin-mediated mitophagy [ 141 , 142 ]. Interestingly, the degradation of the C-terminal fragment of TDP-43 (CTF TDP-25) itself, localizing in mitochondria, is mitophagy-dependent [ 142 ].…”

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

“…In the brains of both patient and healthy cohorts, as well as in animal and cellular models, TDP-43 colocalizes with mitochondrial markers [ 89 , 90 ]. In the last five years, several lines of evidence reported a role for TDP-43 in noncanonical mitochondrial functions that could be grouped in three main classes: (i) interaction with either mitochondrial- or nuclear-encoded nucleic acids affecting mitochondrial functionality [ 22 , 23 , 24 , 25 , 26 ]; (ii) Ca 2+ homeostasis, tethering TDP-43 and mitochondrial impairment to excitotoxicity [ 27 ]; (iii) cellular homeostasis and protein quality control, as TDP-43 was reported to interact with different proteins involved in mitochondrial unfolded protein response (UPR mt ) and autophagy-related pathways [ 28 , 29 , 30 , 31 ]. Alteration in these functions ultimately affects mitochondrial inner membrane potential (m∆Φ), ATP synthesis, oxygen consumption rate, and/or ROS production, resulting in mitochondrial damage and energetic imbalance [ 28 , 29 , 30 , 31 ].…”

“…TDP-43 overexpression reduced the amount of the autophagic marker LC3-II upon treatment with the autophagy inducer CCCP, suggesting the involvement of TDP-43 in the regulation of mitophagy. Parkin-mediated mitophagy was investigated by Jun et al using cortical neurons overexpressing TDP-43 CTF-25 [ 29 ]. In this model, CTF-25 associates with Mitofusin-2 in damaged mitochondria and is related to the reduction in m∆Φ.…”

“…Knockdown of mitophagy receptors TAX1BP, OPTN, or NDP52 resulted in an increased amount of insoluble CTF-25, suggesting that the fragment activates mitophagy and is directly degraded by this pathway. Researchers further explored the role of the motor protein Myosin IIB, showing the involvement of its ATPase activity for the association with mitochondria damaged by CTF-25 [ 29 ].…”