Phosphorylation of MCAD selectively rescuesPINK1deficiencies in behavior and metabolism

Abstract

PTEN-induced putative kinase 1 (PINK1) is a mitochondria-targeted kinase whose mutations are a cause of Parkinson’s disease. We set out to better understand PINK1’s effects on mitochondrial proteins in vivo. Using an unbiased phosphoproteomic screen in Drosophila, we found that PINK1 mediates the phosphorylation of MCAD, a mitochondrial matrix protein critical to fatty acid metabolism. By mimicking phosphorylation of this protein in a PINK1 null background, we restored PINK1 null’s climbing, flight, thorax, and wing deficiencies. Owing to MCAD’s role in fatty acid metabolism, we examined the metabolic profile of PINK1 null flies, where we uncovered significant disruptions in both acylcarnitines and amino acids. Some of these disruptions were rescued by phosphorylation of MCAD, consistent with MCAD’s rescue of PINK1 null’s organismal phenotypes. Our work validates and extends the current knowledge of PINK1, identifies a novel function of MCAD, and illuminates the need for and effectiveness of metabolic profiling in models of neurodegenerative disease.

Dendritic Cells Require PINK1-Mediated Phosphorylation of BCKDE1α to Promote Fatty Acid Oxidation for Immune Function

“…Our data identified PINK1 as a critical regulator of BCAA catabolism, whereas previously PINK1 is shown to critically regulate FAO (71). This led to the question of whether PINK1 via BCAAs contribute to FAO.…”

Metabolomics provide new insights into mechanisms of Wolbachia-induced paternal defects in Drosophila melanogaster

“…Wolbachia-infected male flies exhibited higher levels of TG, as well as many other intermediate products of fatty acid metabolism, such as C14, C16 and C18, than those in uninfected flies. Consistently, Wolbachia infection significantly up-regulated the mRNA levels of Dbi and Mcad encoding acyl-CoA binding protein 2 and acyl-CoA dehydrogenase involved in fatty acid beta-oxidation, respectively [38,49,50]. Wolbachia also lack key biosynthesis genes for lipid metabolism and have to heavily utilise host lipids to serve their own propagation [45,46,51,52].…”

“…The protein Dbi, also known as Acbp2 (Acyl-CoA binding protein 2), was predicted to have fatty-acyl-CoA binding activity. The mitochondrial matrix protein Mcad was reported to be able to catalyze the first reaction of mitochondrial fatty acid beta-oxidation [38]. Thus, we speculated that they may co-regulate the host fatty acid metabolism after Wolbachia infection.…”

FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply

“…In this regard, it is similar to the reversible change in kinesin–Miro interaction that underlies Ca 2+ -mediated arrest of mitochondria or the transient shedding of motor proteins that occurs during mitosis ( Chung et al, 2016 ; Wang and Schwarz, 2009 ) or in response to inhibitory substrates for axon growth ( Kalinski et al, 2019 ). The FHL2-dependent mechanism stands in contrast to the irreversible dissolution of the motor–adaptor complex that occurs when the PINK1/Parkin pathway causes the degradation of Miro on damaged mitochondria ( Course et al, 2018 ; Newman and Shadel, 2018 ; Pickrell and Youle, 2015 ; Wang et al, 2011 ). Elucidating the different ways by which the motor–adaptor complex, and thereby mitochondrial motility, is fine-tuned is essential to explain the normal distribution of mitochondria and to understand the pathological states that arise from its misregulation ( Devine and Kittler, 2018 ; Mattson et al, 2008 ; Misgeld and Schwarz, 2017 ; Pickrell and Youle, 2015 ; Schwarz, 2013 ; Vanhauwaert et al, 2019 ).…”