Neuroprotective effects of ATPase inhibitory factor 1 preventing mitochondrial dysfunction in Parkinson's disease

Inhyeok Chung,Hyeon Soo Kim,Ji Hyung Chung,Su Min Hah,Jun Kang,Juhee Lee,Heyyoung Kim,Han-A Park,Min-Jeong Shin,Won-Seok Choi

doi:10.1038/s41598-022-07851-8

Abstract

Mitochondrial dysfunction is a key element in the progression of Parkinson’s disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. ATPase inhibitory factor 1 (IF1) is a regulator of mitochondrial energy metabolism. IF1 binds directly to the F1Fo ATP synthase and prevents ATP wasting during compromised energy metabolism. In this study, we found treatment with IF1 protects mitochondria against PD-like insult in vitro. SH-SY5Y cells treated with IF1 were resistant to loss of ATP and mitochondrial inner membrane potential during challenge with rotenone, an inhibitor of complex I in the ETC. We further demonstrated that treatment with IF1 reversed rotenone-induced superoxide production in mitochondria and peroxide accumulation in whole cells. Ultimately, IF1 decreased protein levels of pro-apoptotic Bax, cleaved caspase-3, and cleaved PARP, rescuing SH-SY5Y cells from rotenone-mediated apoptotic death. Administration of IF1 significantly improved the results of pole and hanging tests performed by PD mice expressing human α-synuclein. This indicates that IF1 mitigates PD-associated motor deficit. Together, these findings suggest that IF1 exhibits a neuroprotective effect preventing mitochondrial dysfunction in PD pathology.

Highlights

Mitochondrial dysfunction is a key element in the progression of Parkinson’s disease (PD)
We found that treatment with inhibitory factor 1 (IF1) protects mitochondria from PD-like insults and prevents depletion of energy, loss of mitochondrial potential, accumulation of reactive oxygen species (ROS), and activation of apoptotic signaling in dopaminergic cells in vitro
It is well described that inefficient operation of the electron transport chain (ETC) contributes generation of mitochondrial ROS32

Summary

Introduction

Mitochondrial dysfunction is a key element in the progression of Parkinson’s disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. Administration of IF1 significantly improved the results of pole and hanging tests performed by PD mice expressing human α-synuclein This indicates that IF1 mitigates PD-associated motor deficit. Mitochondria play central roles in regulating neuronal energy metabolism via the electron transport chain (ETC). The exact mechanisms of IF1 in mitochondrial function are still disputed, its role in inhibiting the hydrolytic activity of the F 1Fo ATP synthase helps cells prevent ATP wasting during de-energized conditions[18–20]. We found that IF1 rescues dopaminergic cells from rotenone-induced loss of cellular energy, generation of mitochondrial ROS, and activation of apoptosis in vitro. Our results suggest that IF1 exhibits neuroprotective roles in PD pathology by regulating mitochondrial function

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Conclusion