Research Paper Volume 14, Issue 4 pp 1651—1664
Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients
- 1 Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy
- 2 Department of Experimental Medicine, Tor Vergata University, Rome 00133, Italy
- 3 Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome 00167, Italy
- 4 Department of Science, LIME, University Roma Tre, Rome 00146, Italy
- 5 IRCCS Fondazione Santa Lucia, Rome 00179, Italy
Received: November 22, 2021 Accepted: February 14, 2022 Published: February 23, 2022
https://doi.org/10.18632/aging.203910How to Cite
Copyright: © 2022 Murdocca et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
Abbreviations
FIB/SEM: Focused Ion Beam/Scanning Electron Microscopy; TEM: Transmission Electron Microscopy; PGC-1a: peroxisome proliferator-activated receptor gamma co-activator 1a; ROS: reactive oxygen species; DDR: DNA damage response; HGPS: Hutchinson- Gilford Progeroid Syndrome; MTX2: Metaxin-2; CM-H2DCFDA: chloromethyl derivate of 2′,7′-dichlorodihydrofluorescein diacetate; MnSOD: Mn-dependent superoxide dismutase; MDPL: Mandibular hypoplasia, Deafness, Progeroid features and Lipodystrophy Syndrome; Polδ: polymerase delta; DM1: Myotonic Dystrophy type 1; RT: real-time reverse transcription; PCR: polymerase chain reaction; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HGB: hemoglobin subunit beta; OMM: outer mitochondrial membrane; HDFs: human dermal fibroblasts; Met: metformin; MN: micronuclei; NA: aberrant nuclear alteration; Untreat: untreated cells.