Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile

Yongsung Kim, Xinde Zheng, Zoya Ansari, Mark C. Bunnell, Joseph R. Herdy, Larissa Traxler, Hyungjun Lee, Apua C.M. Paquola, Chrysanthi Blithikioti, Manching Ku, Johannes C.M. Schlachetzki, Jürgen Winkler, Frank Edenhofer, Christopher K. Glass, Andres A. Paucar, Baptiste N. Jaeger, Son Pham, Leah Boyer, Benjamin C. Campbell, Tony HunterJerome Mertens, Fred H. Gage

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondria are a major target for aging and are instrumental in the age-dependent deterioration of the human brain, but studying mitochondria in aging human neurons has been challenging. Direct fibroblast-to-induced neuron (iN) conversion yields functional neurons that retain important signs of aging, in contrast to iPSC differentiation. Here, we analyzed mitochondrial features in iNs from individuals of different ages. iNs from old donors display decreased oxidative phosphorylation (OXPHOS)-related gene expression, impaired axonal mitochondrial morphologies, lower mitochondrial membrane potentials, reduced energy production, and increased oxidized proteins levels. In contrast, the fibroblasts from which iNs were generated show only mild age-dependent changes, consistent with a metabolic shift from glycolysis-dependent fibroblasts to OXPHOS-dependent iNs. Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs. Our data indicate that iNs are a valuable tool for studying mitochondrial aging and support a bioenergetic explanation for the high susceptibility of the brain to aging. Kim et al. compared mitochondrial features in aging human fibroblasts and directly induced neurons (iNs). They find that only iNs display severe signs of mitochondrial aging defects and show that the metabolic shift during fibroblast-to-neuron conversion renders iNs particularly vulnerable to mitochondrial aging.

Original languageEnglish (US)
Pages (from-to)2550-2558
Number of pages9
JournalCell Reports
Volume23
Issue number9
DOIs
StatePublished - May 29 2018

Keywords

  • aging
  • directly converted induced neurons
  • glycolysis
  • metabolic shift
  • mitochondria
  • mitochondrial aging
  • neurodegenerative disease
  • oxidative phosphorylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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