Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging

Jyung Mean Son; Ehab H Sarsour; Anurag Kakkerla Balaraju; Jenna Fussell; Amanda L Kalen; Brett A Wagner; Garry R Buettner; Prabhat C Goswami

doi:10.1111/acel.12649

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Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging

Journal article

Open access

Peer reviewed

Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging

Jyung Mean Son, Ehab H Sarsour, Anurag Kakkerla Balaraju, Jenna Fussell, Amanda L Kalen, Brett A Wagner, Garry R Buettner and Prabhat C Goswami

Aging cell, Vol.16(5), pp.1136-1145

10/2017

DOI: 10.1111/acel.12649

PMCID: PMC5595680

PMID: 28758339

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Abstract

Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle. This study investigated whether changes in metabolism occur during aging of quiescent normal human fibroblasts (NHFs) and the mechanisms that regulate these changes. Bioenergetics measurements were taken in quiescent NHFs from younger (newborn, 3-day, 5-month, and 1-year) and older (58-, 61-, 63-, 68-, and 70-year) healthy donors as well as NHFs from the same individual at different ages (29, 36, and 46 years). Results show significant changes in cellular metabolism during aging of quiescent NHFs: Old NHFs exhibit a significant decrease in glycolytic flux and lactate levels, and increase in oxygen consumption rate (OCR) and ATP levels compared to young NHFs. Results from the Seahorse XF Cell Mito Stress Test show that old NHFs with a lower Bioenergetic Health Index (BHI) are more prone to oxidative stress compared to young NHFs with a higher BHI. The increase in OCR in old NHFs is associated with a shift in mitochondrial dynamics more toward fusion. Genetic knockdown of mitofusin 1 (MFN1) and optic atrophy 1 (OPA1) in old NHFs decreased OCR and shifted metabolism more toward glycolysis. Downregulation of MFN1 and OPA1 also suppressed the radiation-induced increase in doubling time of NHFs. In summary, results show that a metabolic shift from glycolysis in young to mitochondrial respiration in old NHFs occurs during chronological lifespan, and MFN1 and OPA1 regulate this process.

Mitochondrial Dynamics

RNA, Small Interfering - genetics

Mitochondrial Membrane Transport Proteins - antagonists & inhibitors

Humans

Middle Aged

Infant

GTP Phosphohydrolases - antagonists & inhibitors

Mitochondrial Membrane Transport Proteins - genetics

Glycolysis - genetics

Cell Respiration - genetics

Aging - genetics

Mitochondria - genetics

Cell Division

Adult

Infant, Newborn

Fibroblasts - metabolism

Mitochondrial Membrane Transport Proteins - metabolism

Signal Transduction

Cells, Cultured

Gene Expression Regulation

Oxidative Phosphorylation

Oxygen Consumption

Mitochondria - metabolism

GTP Phosphohydrolases - metabolism

GTP Phosphohydrolases - genetics

Aged

Fibroblasts - cytology

Aging - metabolism

RNA, Small Interfering - metabolism

Details

Title: Subtitle: Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging
Creators: Jyung Mean Son - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Ehab H Sarsour - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Anurag Kakkerla Balaraju - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Jenna Fussell - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Amanda L Kalen - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Brett A Wagner - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Garry R Buettner - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Prabhat C Goswami - Free Radical and Radiation Biology Division, Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Aging cell, Vol.16(5), pp.1136-1145
DOI: 10.1111/acel.12649
PMID: 28758339
PMCID: PMC5595680
NLM abbreviation: Aging Cell
ISSN: 1474-9718
eISSN: 1474-9726
Publisher: England
Grant note: T35 HL007485 / NHLBI NIH HHS R01 CA111365 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 10/2017
Academic Unit: Radiation Oncology
Record Identifier: 9984047679802771

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