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

Date Published: July 31, 2017

Publisher: John Wiley and Sons Inc.

Author(s): Jyung Mean Son, Ehab H. Sarsour, Anurag Kakkerla Balaraju, Jenna Fussell, Amanda L. Kalen, Brett A. Wagner, Garry R. Buettner, Prabhat C. Goswami.


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.

Partial Text

Aging is a critical risk factor for numerous health issues and successful therapy outcome. The average global life expectancy has increased approximately 50% over the last 100 years (Vincent & Velkoff, 2010). Unfortunately, the increase in life expectancy is also a significant risk factor for various age‐related health issues (e.g., cardiovascular disease, cancer, diabetes, and stroke). Therefore, additional research is needed to understand more about the basic biology of aging.

Chronological lifespan and replicative lifespan are two types of cellular aging (Munro et al., 2001; Sarsour et al., 2005, 2012; Longo et al., 2012). Our earlier results (Sarsour et al., 2010, 2012) and that mitochondria being the hub of cellular metabolism led us to investigate whether changes in cellular metabolism can regulate chronological lifespan. Results showed that cellular metabolism shifts more toward mitochondrial respiration during aging. An age‐related increase in mitochondrial respiration negatively impacts NHFs’ ability to cope with oxidative stress. Mitochondrial fusion proteins, MFN1 and OPA1 regulate both of these processes: mitochondrial respiration and response to oxidative stress.

Additional details of the methods are included in the Data S1 (Supporting information).

J.S. and P.C.G. formulated the concept, experimental design, and data analysis of this research project, and wrote the manuscript. J.S., E.H.S., A.K., J.F., A.L.K., and B.A.W. performed experiments and assisted P.C.G with data analysis. G.R.B assisted with the design and data analysis for the Seahorse XF96 measurements of bioenergetics.

This work was supported by the NIH (2R01‐CA111365, CA169046, and P30 CA086862) and Holden Comprehensive Cancer Center funding.

All authors declare no conflict of interest.




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