Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Abstract

Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy is a rare, genetic, premature aging disease named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. In previous in vitro studies, we have already described several hallmarks of aging, including genetic damage, telomere shortening, cell senescence and proliferation defects. Since a clear connection has been reported between telomere shortening and mitochondria malfunction to initiate the aging process, we explored the role that mitochondrial metabolism and activity play in pathogenesis of MDPL Syndrome, an aspect that has not been addressed yet. We thus evaluated mtDNA copy number, assessing a significant decrease in mutated cells. The expression level of genes related to mitochondrial biogenesis and activity also revealed a significant reduction, highlighting a mitochondrial dysfunction in MDPL cells. Even the expression levels of mitochondrial marker SOD2, as assessed by immunofluorescence, were reduced. The decrease in this antioxidant enzyme correlated with increased production of mitochondrial ROS in MDPL cells, compared to WT. Consistent with these data, Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) analysis revealed in MDPL cells fewer mitochondria, which also displayed morphological abnormalities. Accordingly, we detected autophagic vacuoles containing partially digested mitochondria. Overall, our results demonstrate a dramatic impairment of mitochondrial biogenesis and activity in MDPL Syndrome. Administration of Metformin, though unable to restore mitochondrial impairment, proved efficient in rescuing nuclear abnormalities, suggesting its use to specifically ameliorate the premature aging phenotype.www.aging-us.com AGINGG0/G1 phase. Furthermore, telomere shortening was faster in MDPL cells, proposing their malfunction as a relevant trait in MDPL syndrome.Current papers have reported that telomere shortening may also influence mitochondria activity through many pathways to begin the aging process, among which the nuclear-mitochondrial signalling [3]. Adaptive response to such damage involves peroxisome proliferatoractivated receptor gamma co-activator 1a (PGC-1a), a master regulator of mitochondrial biogenesis and activity, which is activated by SIRT1. In turn, PGC-1a induces the expression of mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2).

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

“…We found that the immortalized cell lines from Pt#1, 2, and 16 (POLK) showed better metabolic capacity compared to control cell lines. Intriguingly, patients with mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy, characterized by germline PGVs in POLD1, also present with mitochondrial dysfunction and metabolic abnormalities (15,47,48). Conversely, some familial RCC genes (such as FH, VHL, PBMR1, and SDHx) have also been implicated in suppression of DSBs and in replication stress (49)(50)(51)(52), based on mechanisms that are not well understood.…”