Cardiolipin remodeling by ALCAT1 links mitochondrial dysfunction to Parkinson's diseases.

Abstract

Cardiolipin (CL) is a mitochondrial signature phospholipid that is required for membrane structure, respiration, dynamics, and mitophagy. Oxidative damage of CL by reactive oxygen species is implicated in the pathogenesis of Parkinson's disease (PD), but the underlying cause remains elusive. This work investigated the role of ALCAT1, an acyltransferase that catalyzes pathological remodeling of CL in various aging-related diseases, in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP). We show that MPTP treatment caused oxidative stress, mtDNA mutations, and mitochondrial dysfunction in the midbrain. In contrast, ablation of the ALCAT1 gene or pharmacological inhibition of ALCAT1 prevented MPTP-induced neurotoxicity, apoptosis, and motor deficits. ALCAT1 deficiency also mitigated mitochondrial dysfunction by modulating DRP1 translocation to the mitochondria. Moreover, pharmacological inhibition of ALCAT1 significantly improved mitophagy by promoting the recruitment of Parkin to dysfunctional mitochondria. Finally, ALCAT1 expression was upregulated by MPTP and by α-synucleinopathy, a key hallmark of PD, whereas ALCAT1 deficiency prevented α-synuclein oligomerization and S-129 phosphorylation, implicating a key role of ALCAT1 in the etiology of mouse models of PD. Together, these findings identify ALCAT1 as a novel drug target for the treatment of PD.

• Authors: Chengjie Song, Jun Zhang, Shasha Qi, Zhen Liu, Xiaoyang Zhang, Yue Zheng, John-Paul Andersen, Weiping Zhang, Randy Strong, Paul Anthony Martinez, Nicolas Musi, Jia Nie, Yuguang Shi
• Journal: Aging cell (Aging Cell) Vol. 18 Issue 3 Pg. e12941 (06 2019) ISSN: 1474-9726 [Electronic] England
• PMID: 30838774 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Chemical References

• Cardiolipins
• Reactive Oxygen Species
• alpha-Synuclein
• Acyltransferases
• lysocardiolipin acyltransferase, mouse
• Ubiquitin-Protein Ligases
• parkin protein

Topics

• Acyltransferases (antagonists & inhibitors, genetics, metabolism)
• Animals
• Apoptosis (drug effects, genetics)
• Cardiolipins (chemistry, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Humans
• Locomotion (drug effects, genetics)
• MPTP Poisoning (metabolism)
• Mice
• Mice, Transgenic
• Mitochondria (genetics, metabolism)
• Mitochondrial Dynamics (drug effects, genetics)
• Mitophagy (drug effects, genetics)
• Nerve Degeneration (genetics, metabolism, mortality)
• Phosphorylation
• Reactive Oxygen Species (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• alpha-Synuclein (chemistry, metabolism)