Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion.
Tian Liu, Liam Wetzel, Zexi Zhu, Pavan Kumaraguru, Viraj Gorthi, Yan Yan, Mohammed Zaheen Bukhari, Aizara Ermekbaeva, Hanna Jeon, Teresa R Kee, Jung-A Alexa Woo, David E Kang
Author Information
Tian Liu: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Liam Wetzel: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Zexi Zhu: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Pavan Kumaraguru: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Viraj Gorthi: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Yan Yan: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Mohammed Zaheen Bukhari: Byrd Alzheimer's Center & Research Institute, Department of Molecular Medicine, USF Health Morsani College of Medicine, Tampa, FL 33613, USA.
Aizara Ermekbaeva: Byrd Alzheimer's Center & Research Institute, Department of Molecular Medicine, USF Health Morsani College of Medicine, Tampa, FL 33613, USA.
Hanna Jeon: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Teresa R Kee: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. ORCID
Jung-A Alexa Woo: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
David E Kang: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) is a nuclear-encoded mitochondrial protein which is primarily mutated in the spectrum of familial and sporadic amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD). Endogenous CHCHD10 levels decline in the brains of ALS-FTD patients, and the CHCHD10 mutation in induces dominant toxicity together with PTEN-induced kinase 1 (PINK1), a protein critical for the induction of mitophagy. However, whether and how CHCHD10 variants regulate mitophagy flux in the mammalian brain is unknown. Here, we demonstrate through in vivo and in vitro models, as well as human FTD brain tissue, that ALS/FTD-linked CHCHD10 mutations (R15L and S59L) impair mitophagy flux and mitochondrial Parkin recruitment, whereas wild-type CHCHD10 (CHCHD10) normally enhances these measures. Specifically, we show that CHCHD10 and CHCHD10 mutations reduce PINK1 levels by increasing PARL activity, whereas CHCHD10 produces the opposite results through its stronger interaction with PARL, suppressing its activity. Importantly, we also demonstrate that FTD brains with TAR DNA-binding protein-43 (TDP-43) pathology demonstrate disruption of the PARL-PINK1 pathway and that experimentally impairing mitophagy promotes TDP-43 aggregation. Thus, we provide herein new insights into the regulation of mitophagy and TDP-43 aggregation in the mammalian brain through the CHCHD10-PARL-PINK1 pathway.
