UQCRC1 engages cytochrome c for neuronal apoptotic cell death
Yu-Chien Hung,
Kuan-Lin Huang,
Po-Lin Chen,
Jeng-Lin Li,
Serena Huei-An Lu,
Jui-Chih Chang,
Han-Yi Lin,
Wen-Chun Lo,
Shu-Yi Huang,
Tai-Ting Lee,
Tai-Yi Lin,
Yuzuru Imai,
Nobutaka Hattori,
Chin-San Liu,
Su-Yi Tsai,
Chun-Hong Chen,
Chin-Hsien Lin,
Chih-Chiang Chan
Affiliations
Yu-Chien Hung
Graduate Institute of Physiology, National Taiwan University, Taipei 100, Taiwan
Kuan-Lin Huang
Graduate Institute of Physiology, National Taiwan University, Taipei 100, Taiwan
Po-Lin Chen
Graduate Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 100, Taiwan; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
Jeng-Lin Li
Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan
Serena Huei-An Lu
Department of Life Science, National Taiwan University, Taipei 106, Taiwan
Jui-Chih Chang
Center of Regenerative Medicine and Tissue Repair, Changhua Christian Hospital, Changhua 500, Taiwan; General Research Laboratory of Research Department, Changhua Christian Hospital, Changhua 500, Taiwan
Han-Yi Lin
Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan
Wen-Chun Lo
Graduate Institute of Physiology, National Taiwan University, Taipei 100, Taiwan
Shu-Yi Huang
Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan
Tai-Ting Lee
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
Tai-Yi Lin
Department of Medicine, National Taiwan University, Taipei 100, Taiwan
Yuzuru Imai
Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Research for Parkinson’s Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Nobutaka Hattori
Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; Department of Research for Parkinson’s Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Chin-San Liu
Department of Vascular and Genomic Center, Changhua Christian Hospital, Changhua 500, Taiwan; Department of Neurology, Changhua Christian Hospital, Changhua 500, Taiwan; Graduate Institute of Integrated Medicine, College of Chinese Medicine, Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung 404, Taiwan
Su-Yi Tsai
Department of Life Science, National Taiwan University, Taipei 106, Taiwan
Chun-Hong Chen
Graduate Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 100, Taiwan; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
Chin-Hsien Lin
Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan; Corresponding author
Chih-Chiang Chan
Graduate Institute of Physiology, National Taiwan University, Taipei 100, Taiwan; Corresponding author
Summary: Human ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) is an evolutionarily conserved core subunit of mitochondrial respiratory chain complex III. We recently identified the disease-associated variants of UQCRC1 from patients with familial parkinsonism, but its function remains unclear. Here we investigate the endogenous function of UQCRC1 in the human neuronal cell line and the Drosophila nervous system. Flies with neuronal knockdown of uqcrc1 exhibit age-dependent parkinsonism-resembling defects, including dopaminergic neuron reduction and locomotor decline, and are ameliorated by UQCRC1 expression. Lethality of uqcrc1-KO is also rescued by neuronally expressing UQCRC1, but not the disease-causing variant, providing a platform to discern the pathogenicity of this mutation. Furthermore, UQCRC1 associates with the apoptosis trigger cytochrome c (cyt-c), and uqcrc1 deficiency increases cyt-c in the cytoplasmic fraction and activates the caspase cascade. Depleting cyt-c or expression of the anti-apoptotic p35 ameliorates uqcrc1-mediated neurodegeneration. Our findings identify a role for UQCRC1 in regulating cyt-c-induced apoptosis.
