Research Paper Volume 6, Issue 4 pp 296—310

Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians

Gianluca Sgarbi1, *,, Paola Matarrese2,3, *,, Marcello Pinti4, , Catia Lanzarini5, , Barbara Ascione2, , Lara Gibellini4, , Emi Dika5, , Annalisa Patrizi5, , Chiara Tommasino2, , Miriam Capri5,6, , Andrea Cossarizza7, , Alessandra Baracca1, , Giorgio Lenaz1, , Giancarlo Solaini1, , Claudio Franceschi5,6,8,9, , Walter Malorni2,10, , Stefano Salvioli5,6, ,

  • 1 DIBINEM, Department of Biomedical and Neuromotor Sciences University of Bologna, 40126 Bologna, Italy
  • 2 Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy
  • 3 Center of Integrated Metabolomics, 00161 Rome, Italy
  • 4 Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
  • 5 DIMES, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy
  • 6 CIG, Interdepartmental Center “Luigi Galvani”, University of Bologna, 40126 Bologna, Italy
  • 7 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
  • 8 IRCCS Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy
  • 9 CNR-ISOF, Institute of Organic Synthesis and Photoreactivity, 40129 Bologna, Italy
  • 10 San Raffaele Institute Sulmona, Viale dell'Agricoltura 1, 67039 Sulmona (L'Aquila), Italy
* Equal contribution

Received: April 14, 2014       Accepted: April 26, 2014       Published: April 30, 2014      

https://doi.org/10.18632/aging.100654
How to Cite

Abstract

Mitochondria have been considered for long time as important determinants of cell aging because of their role in the production of reactive oxygen species. In this study we investigated the impact of mitochondrial metabolism and biology as determinants of successful aging in primary cultures of fibroblasts isolated from the skin of long living individuals (LLI) (about 100 years old) compared with those from young (about 27 years old) and old (about 75 years old) subjects. We observed that fibroblasts from LLI displayed significantly lower complex I-driven ATP synthesis and higher production of H2O2 in comparison with old subjects. Despite these changes, bioenergetics of these cells appeared to operate normally. This lack of functional consequences was likely due to a compensatory phenomenon at the level of mitochondria, which displayed a maintained supercomplexes organization and an increased mass. This appears to be due to a decreased mitophagy, induced by hyperfused, elongated mitochondria. The overall data indicate that longevity is characterized by a preserved bioenergetic function likely attained by a successful mitochondria remodeling that can compensate for functional defects through an increase in mass, i.e. a sort of mitochondrial “hypertrophy”.

Abbreviations

CCCP: carbonyl cyanide m-chlorophenyl hydrazone; CS: citrate synthase; DFs: dermal fibroblasts; DRP1: dynamin-related protein 1; GSH: reduced glutathione; H2DCF-DA: 2,7-dicholorodihydrofluorescein diacetate; IVM: intensified video microscopy; HBSS: Hank's Balanced Salt Solution; HE: hydroethidine; JC-1: 5,5,6,60-tetra-chloro-1,10,3,30-tetraethylbenzimidazolyl-carbocyanine iodide; LLI: long-living individuals; LAMP1: lysosomal-associated membrane protein 1; 3-MA: 3-methyl adenine; TOM20: mitochondrial import receptor subunit TOM20 homolog; Mdivi1: anti-, mitochondrial division inhibitor 1; mtDNA: mitochondrial DNA; Mfn1: mitofusin 1; MMP: mitochondrial membrane potential; MTG: mitotracker Green; MBB: monobromobimane; O2: superoxide anion; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; SD: standard deviation; SEM: standard error of the mean; TOPRO: TO-PRO-3 iodide.