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Cell Rep. 2018 May 29;23(9):2550-2558. doi: 10.1016/j.celrep.2018.04.105.

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

Author information

1
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
3
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Institute of Molecular Biology, Leopold-Franzens-University Innsbruck, Technikerstraβe 25, 6020 Innsbruck, Austria.
4
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Lieber Institute for Brain Development, 855 North Wolfe Street, Suite 300, Baltimore, MD 21205, USA.
5
Next Generation Sequencing Core, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Clinic for Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, University of Freiburg Medical Center, Mathildenstraβe 1, 79106 Freiburg im Breisgau, Germany.
6
Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
7
Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
8
Institute of Molecular Biology, Leopold-Franzens-University Innsbruck, Technikerstraβe 25, 6020 Innsbruck, Austria.
9
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
10
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Institute of Molecular Biology, Leopold-Franzens-University Innsbruck, Technikerstraβe 25, 6020 Innsbruck, Austria. Electronic address: jmertens@salk.edu.
11
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: gage@salk.edu.

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.

KEYWORDS:

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

PMID:
29847787
DOI:
10.1016/j.celrep.2018.04.105
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