Autophagy
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VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). ⋯ We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells.
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Damaged or dysfunctional mitochondria are toxic to the cell by producing reactive oxygen species and releasing cell death factors. Therefore, timely removal of these organelles is critical to cellular homeostasis and viability. Mitophagy is the mechanism of selective degradation of mitochondria via autophagy. ⋯ Moreover, ischemic AKI is aggravated in pink1 andpark2 single- as well as double-knockout mice. Mechanistically, Pink1 and Park2 deficiency enhances mitochondrial damage, reactive oxygen species production, and inflammatory response. Taken together, these results indicate that PINK1-PARK2-mediated mitophagy plays an important role in mitochondrial quality control, tubular cell survival, and renal function during AKI.
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Loss-of-function mutations in the genes encoding PRKN/parkin and PINK1 cause autosomal recessive Parkinson disease (PD). Seminal work in Drosophila revealed that loss of park/parkin and Pink1 causes prominent mitochondrial pathology in flight muscle and, to a lesser extent, in dopaminergic neurons. Subsequent studies in cultured mammalian cells discovered a crucial role for PRKN/PARK2 and PINK1 in selective macroautophagic removal of mitochondria (mitophagy). ⋯ Moreover, this age-dependent rise depends on park and Pink1. Our data also suggested that some aspects of the mitochondrial phenotype of park- and Pink1-deficient flies are independent of the mitophagy defect, and that park and Pink1 may have multiple functions in the regulation of the integrity of these organelles. Here, we discuss implications of these findings as well as possible future applications of the mt-Keima fly model.
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Mitochondrial damage triggers mitochondrial quality control pathways, which act to ensure the health of the mitochondrial network. The turnover of damaged mitochondria by mitophagy is initiated by the Parkinson disease-linked genes PRKN and PINK1, and we recently investigated the role that interorganellar contact sites between the endoplasmic reticulum (ER) and the outer mitochondrial membrane (OMM) play in this pathway. ⋯ PINK1, PRKN and the AAA-ATPase VCP disrupt contact between mitochondria and the ER via MFN2 ubiquitination, retrotranslocation and turnover from the mitochondrial membrane. Our study provides insight into the role of OMM remodeling in mitophagy.
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HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy.
While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation. Our results demonstrated that exposure of mouse primary microglia to HIV-1 TAT resulted in cellular activation involving altered mitochondrial membrane potential that was accompanied by accumulation of damaged mitochondria. ⋯ Interestingly, HIV-1 TAT-mediated activation of microglia was associated with decreased rate of extracellular acidification and mitochondrial oxygen consumption and increased expression of proinflammatory cytokines, such as Tnf, Il1b, and Il6. HIV-1 TAT-mediated defective mitophagy leading to microglial activation was further validated in vivo in the brains of HIV-1 transgenic rats. In conclusion, HIV-1 TAT activates microglia by increasing mitochondrial damage via defective mitophagy.