Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model - PubMed (original) (raw)

Comparative Study

Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model

Satomi Miwa et al. Aging Cell. 2008 Dec.

Abstract

'Mitochondrial dysfunction', which may result from an accumulation of damaged mitochondria in cells due to a slowed-down rate of mitochondrial turnover and inadequate removal of damaged mitochondria during aging, has been implicated as both cause and consequence of the aging process and a number of age-related pathologies. Despite growing interest in mitochondrial function during aging, published data on mitochondrial turnover are scarce, and differ from each other by up to one order of magnitude. Here we demonstrate that re-utilization of the radioactively labelled precursor in pulse-chase assays is the most likely cause of significant overestimation of mitochondrial turnover rates. We performed a classic radioactive label pulse-chase experiment using (14)C NaHCO(3), whose (14)C is incorporated into various amino acids, to measure mitochondrial turnover in mouse liver. In this system, the activity of the urea cycle greatly limited arginine dependent label re-utilization, but not that of other amino acids. We used information from tissues that do not have an active urea cycle (brain and muscle) to estimate the extent of label re-utilization with a dynamic mathematical model. We estimated the actual liver mitochondrial half life as only 1.83 days, and this decreased to 1.16 days following 3 months of dietary restriction, supporting the hypothesis that this intervention might promote mitochondrial turnover as a part of its beneficial effects.

PubMed Disclaimer

Figures

Fig. 1

A single exponential decay model is not adequate to measure mouse liver mitochondrial half life. (A) Changes in specific activity of 14C in liver mitochondria from control mice with time. Results from two sets of independent experiments are shown (full and open circles). Each data point represents an individual animal. (B) Effect of chase period on half lives of mitochondria from dietary restricted (DR) and control mice. Apparent half life time of mitochondria λ depends on the chase period if calculated as single exponential decay by logarithmic transfer. Data are mean ± SEM. • = DR; formula image = controls. These estimates in control animals are in good agreement with published data with corresponding chase periods (Lipsky & Pedersen, 1981; Lavie et al., 1982; Saikumar & Kurup, 1985).

Fig. 2

Liver mitochondrial half life is short and decreases further by dietary restriction. (A) Observed (circles) and median simulated (solid lines) decay of specific activity of 14C label in liver (left), muscle (centre) and brain (right) mitochondria. Top panels are from 6-month-old control mice and the bottom panels are from mice dietary restricted for 3 months. Dashed lines are 5% and 95% quantiles of samples from simulated label count posterior distributions (20 000 simulations sampled after discarding 10 000 ‘run-in’ simulations). (B) Posterior frequency distributions of calculated half lives (λFast, in days) of liver mitochondria from control and dietary restricted mice. In 99.96% of the 20 000 sampled simulations λ_DR_ < λ_Control_, which is a statistically significant result. The median values for λ_DR_ and λ_Control_ are 1.16 days and 1.83 days, respectively.

References

1. Aschenbrenner B, Druyan R, Albin R, Rabinowitz M. Haem a, cytochrome c and total protein turnover in mitochondria from rat heart and liver. Biochem. J. 1970;119:157–160. - PMC - PubMed
1. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483–495. - PubMed
1. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 2006;38:515–517. - PubMed
1. Bergamini E, Cavallini G, Donati A, Gori Z. The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically. Biomed. Pharmacother. 2003;57:203–208. - PubMed
1. Bulteau AL, Szweda LI, Friguet B. Mitochondrial protein oxidation and degradation in response to oxidative stress and aging. Exp. Gerontol. 2006;41:653–657. - PubMed

Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model - PubMed (original) (raw)