Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Abstract

SummaryCaloric restriction is the most effective non-genetic intervention to enhance lifespan known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, 2,4-dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and lifespan effects of caloric restriction in healthy mammals.

Mitochondrial uncoupling as a regulator of life history trajectories in birds: An experimental study in the zebra finch

“…Indeed, preliminary in vivo analyses resulted in contrasted findings between what we were observing in birds (present study; P.B., unpublished results in Japanese quails, Coturnix japonica) and results previously reported for mice (Caldeira da Silva et al, 2008), thereby suggesting the need for insights into the effects of DNP at the mitochondrial level.…”

“…Experiments in which individuals were treated with a mitochondrial uncoupler [i.e. the artificial protonophore 2,4-dinitrophenol (DNP)] demonstrated that mild mitochondrial uncoupling increases metabolic rate in Drosophila (Padalko, 2005), Rana temporaria tadpoles (Salin et al, 2012a) and laboratory mice (Caldeira da Silva et al, 2008), and concomitantly decreases oxidative stress levels (mice and tadpoles) and extends lifespan (Drosophila and mice). However, so far no studies have addressed the impact of such an uncoupling treatment on other life-history traits such as growth rate, reproductive performance or immune responsiveness.…”

Oxidative phosphorylation efficiency, proton conductance and reactive oxygen species production of liver mitochondria correlates with body mass in frogs

“…Therefore, previous studies suggest that small endotherms have a lower mitochondrial efficiency than larger species Porter and Brand, 1993;Porter et al, 1996). These allometric relationships echo several experimental studies on (i) organisms treated with chemical uncouplers such as 2,4-dinitrophenol (Toyomizu et al, 1992;Caldeira da Silva et al, 2008;Salin et al, 2012a) or (ii) a genetic line of poultry selected for low feed efficiency (Bottje et al, 1999), showing that mitochondrial efficiency could constrain growth rate and so underpin the variability of M b . However, the question of why mitochondrial inefficiency evolved in an allometric manner among taxa remains an open debate.…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…Conversely, a mild decrease in mitochondrial potential caused by protonophores was shown to increase lifespan in yeast (Barros, Bandy, Tahara, & Kowaltowski, 2004), flies (Padalko, 2005) and mice (Caldeira da Silva, Cerqueira, Barbosa, Medeiros, & Kowaltowski, 2008). This is in accordance with data from Delaney et al.…”