MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A
Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met376 and His380 interactions with Asp725 and Leu727 and controlled by PINK1 kinase–mediated phosphorylation of adjacent MFN2 Ser378. Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg94->Gln94 and MFN2 Thr105->Met105, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105->Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.
This study examines the interaction of GERD and EsD on spirometry in LTRs.
Bronchiolitis obliterans (BOS) remains a major cause of death for lung transplant recipients, and mechanisms that drive BOS remain poorly understood. Genetically encoded deficiencies in mitophagy, a specialized autophagy that targets the removal of damaged mitochondria, have been shown to promote Parkinson's disease, but it is unclear if they play a role in other chronic diseases. Recent work has shown that the rs2241880 mutation in the autophagy regulator ATG16L1 leads to protein instability resulting in deficiency of ATG16L1 in monocyte-derived macrophages.
Esophageal dysmotility can decrease luminal clearance and increase the risk of aspiration and GERD and contribute to allograft dysfunction. We sought to determine the impact of pre-transplant esophageal dysmotility on allograft function, GERD, rejection and survival after lung transplantation.
Esophageal dysmotility is very common in lung transplant recipients and is thought to predispose to allograft injury through higher risk of aspiration. At our center, we routinely test lung transplant recipients for esophageal dysmotility with High Resolution Manometry (HRM) at 3 months post-transplant. We hypothesize that lung transplant recipients (LTRs) with significant esophageal dysmotility are more likely to develop lung injury leading to CLAD and death.
This report investigates the effect of esophageal motility disorders on CLAD after lung transplantation. We hypothesized that esophageal dysmotility will result in more frequent development of CLAD.
This study showed that the presence of Phoenixin 20 promoted neuronal mitochondrial biogenesis in vitro. In cultured neuronal M17 cells, Phoenixin 20 increased the expression of mitochondrial regulators PGC-1 α, NRF-1, and TFAM at both mRNA and protein levels. The treatment of Phoenixin 20 increased the ratio of mitochondrial vs nuclear DNA (mtDNA/nDNA) and the multiple mitochondrial gene expression as revealed by increasing mRNA expression of Tomm22, Timm50, Atp5d, Ndufs3, and protein expression of NDU FB8. At a cellular level, Phoenixin 20 promoted mitochondrial respiratory rate and cellular ATP production. Mechani...
Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes...
Antioxidants&Redox Signaling, Ahead of Print.
Nature Reviews Neurology, Published online: 31 March 2020; doi:10.1038/s41582-020-0353-3Mitochondrial dysfunction manifests in the early stages of Alzheimer disease