TY - JOUR
T1 - ALS-related mutant SOD1 aggregates interfere with mitophagy by sequestering the autophagy receptor optineurin
AU - Tak, Yeong Jin
AU - Park, Ju Hwang
AU - Rhim, Hyangshuk
AU - Kang, Seongman
N1 - Funding Information:
Funding: This research was funded by a National Research Foundation of Korea (NRF) Grant (MEST) (2018R1A2B6001440), Korea University, and a BRL grant (NRF-2015R1A4A1041919) funded by the Ministry of Science, ICT and Future Planning, Republic of Korea.
PY - 2020/10/2
Y1 - 2020/10/2
N2 - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.
AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.
KW - Amyotrophic lateral sclerosis (ALS)
KW - Mitophagy
KW - Optineurin (OPTN)
KW - Superoxide dismutase 1 (SOD1)
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U2 - 10.3390/ijms21207525
DO - 10.3390/ijms21207525
M3 - Article
C2 - 33065963
AN - SCOPUS:85092932407
VL - 21
SP - 1
EP - 17
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 20
M1 - 7525
ER -