Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy

Abstract

Choline kinase is the first step enzyme for phosphatidylcholine (PC) de novo biosynthesis. Loss of choline kinase activity in muscle causes rostrocaudal muscular dystrophy (rmd) in mouse and congenital muscular dystrophy in human, characterized by distinct mitochondrial morphological abnormalities. We performed biochemical and pathological analyses on skeletal muscle mitochondria from rmd mice. No mitochondria were found in the center of muscle fibers, while those located at the periphery of the fibers were significantly enlarged. Muscle mitochondria in rmd mice exhibited significantly decreased PC levels, impaired respiratory chain enzyme activities, decreased mitochondrial ATP synthesis, decreased coenzyme Q and increased superoxide production. Electron microscopy showed the selective autophagic elimination of mitochondria in rmd muscle. Molecular markers of mitophagy, including Parkin, PINK1, LC3, polyubiquitin and p62, were localized to mitochondria of rmd muscle. Quantitative analysis shows that the number of mitochondria in muscle fibers and mitochondrial DNA copy number were decreased. We demonstrated that the genetic defect in choline kinase in muscle results in mitochondrial dysfunction and subsequent mitochondrial loss through enhanced activation of mitophagy. These findings provide a first evidence for a pathomechanistic link between de novo PC biosynthesis and mitochondrial abnormality.

Enhanced mitophagy in Sertoli cells of ethanol-treated rats: morphological evidence and clinical relevance

“…These mitochondria were always enveloped by isolation membranes, engulfed inside AVs and seemed to aggregate around the nuclei of Sertoli cells. The ultrastructural features of the mitophagic vacuoles or mitophagosomes in Sertoli cells of ETR are consistent with the ultrastructural definitions of mitophagy, mentioned in ''Materials and methods'' section of this manuscript (Fortunato et al 2009;Pan et al 2009;Cordero et al 2010;Ding et al 2010;Sansanwal et al 2010;Mitsuhashi et al 2011). Late AVs in Fig.…”

“…Using immunofluorescence microscopy (IFM), Lemasters and colleagues coined the term mitophagy to describe the engulfment of mitochondria into vesicles that are coated with the autophagosome marker LC3 (Kim et al 2007a;Youle and Narendra 2011). Therefore, LC3 is a molecular marker not only for macroautophagy but also for mitophagy (Kim et al 2007a;Ding et al 2010;Sansanwal et al 2010;Mitsuhashi et al 2011). Further studies are required to reveal the presence or absence of specific molecular mechanisms involved in the regulation of mitophagy in the testes of ETR (Youle and Narendra 2011;Mitsuhashi et al 2011).…”

“…Therefore, LC3 is a molecular marker not only for macroautophagy but also for mitophagy (Kim et al 2007a;Ding et al 2010;Sansanwal et al 2010;Mitsuhashi et al 2011). Further studies are required to reveal the presence or absence of specific molecular mechanisms involved in the regulation of mitophagy in the testes of ETR (Youle and Narendra 2011;Mitsuhashi et al 2011).…”

Ca2+ Binding/Permeation via Calcium Channel, CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism

“…The decrease in COXIV protein levels suggests that OXPHOS may be altered in EK muscle. We assayed mitochondrial OXPHOS activity as described by Mitsuhashi et al (17) and found a small, but significant decrease in Complex IV, but not Complex I-III activity (Fig. 4, C and D).…”

Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

“…Genetic studies in mice or humans with defects in coline kinase β, enzyme catalysing the synthesis of PC, demonstrate that reduction of mitochondrial membrane PC content induced enlarged mitochondria, reduced inner membrane potential and caused muscle weakness [20][21][22][23]. The proper lipid composition of the membranes is crucial for membrane-bound protein machineries to maintain optimal mitochondrial biogenesis and function.…”