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.

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

“…In the current study, p-α-Synuclein and α-Synuclein protein were increased in SN and Hippo areas ( Figure 1A and B), which is consistent with former studies. 23,33 In addition, the upregulated p-α-Synuclein mainly localized in the limbic systems such as cortex, polymorph layer of hippocampal, amygdala and VTA (Figure 2A and B). In the cellular level, the p-α-Synuclein localized in the nucleus and cytoplasm in cortex, amygdala, VTA and pyramidal layer of hippocampal CA3, and neurites in polymorph layer of hippocampal CA3.…”

Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects

“…Ablation of ALCAT1 gene or inhibition of ALCAT1 activity by pharmacological agents, prevented MPTP-induced neurotoxicity, mitochondrial dysfunction, apoptosis, and locomotive defects, typical of PD. In addition, pharmacological inhibition of ALCAT1 activity, improved mitophagy by promoting the recruitment of Parkin to dysfunctional mitochondria [128]. These results point to the involvement of ALCAT1 in the etiology of mouse model of PD and identify this enzyme as a potential drug target for treatment of this neurodegenerative disorder.…”

“…PINK1 mutations result in lower levels of CL in mitochondria, associated with oxidative stress and aberrant mitochondrial function [126,127]. Very recently, an involvement of ALCAT1, an enzyme that catalyzes CL remodeling, in mitochondrial dysfunction associated with PD, was suggested [128]. In a mouse model of PD, MPTP treatment resulted in oxidative stress and mitochondrial dysfunction in midbrain.…”

Obesity causes irreversible mitochondria failure in visceral adipose tissue despite successful anti-obesogenic lifestyle-based interventions

“…In this respect, lysocardiolipin acyltransferase 1 (LCLAT1) has been suggested as a pivotal enzyme involved in the pathological remodeling of cardiolipin in various age-related pathological conditions including diet-induced obesity and T2D. Thus, LCLAT1 expression tendency to increase aggravates the vicious cycle among mitochondrial dysfunction, ROS damage, and defects in mitochondrial recycling capacity (29)(30)(31). Therefore, the combination of different data sets not only evidences a deficiency in cristae formation but also suggests a defective clearance of dysfunctional mitochondria as a plausible explanation for this loss of metabolic plasticity.…”