Mitochondria in ageing: there is metabolism beyond the ROS

Abstract

Mitochondria are responsible for a series of metabolic functions. Superoxide leakage from the respiratory chain and the resulting cascade of reactive oxygen species-induced damage, as well as mitochondrial metabolism in programmed cell death, have been intensively studied during ageing in single-cellular and higher organisms. Changes in mitochondrial physiology and metabolism resulting in ROS are thus considered to be hallmarks of ageing. In this review, we address 'other' metabolic activities of mitochondria, carbon metabolism (the TCA cycle and related underground metabolism), the synthesis of Fe/S clusters and the metabolic consequences of mitophagy. These important mitochondrial activities are hitherto less well-studied in the context of cellular and organismic ageing. In budding yeast, they strongly influence replicative, chronological and hibernating lifespan, connecting the diverse ageing phenotypes studied in this single-cellular model organism. Moreover, there is evidence that similar processes equally contribute to ageing of higher organisms as well. In this scenario, increasing loss of metabolic integrity would be one driving force that contributes to the ageing process. Understanding mitochondrial metabolism may thus be required for achieving a unifying theory of eukaryotic ageing.

Oxygen availability strongly affects chronological lifespan and thermotolerance in batch cultures of Saccharomyces cerevisiae

“…These approaches, however, have several drawbacks. Firstly, mitochondria are not only involved in respiration, but also in essential anabolic reactions (e.g., assembly of iron-sulfur complexes, amino acid biosynthesis and long-chain lipid biosynthesis 26). Studies on petite or ρ 0 mutants may therefore cause unwanted ‘side-effects’ resulting from the absence or inefficiency of mitochondrial processes, rather than from direct effects of oxygen or respiration on aging.…”

Rewiring yeast acetate metabolism through MPC1 loss of function leads to mitochondrial damage and decreases chronological lifespan

“…Mitochondrial dysfunctions are intrinsically related to reactive oxygen species (ROS) of which superoxide anion is one of the most potentially harmful. This radical derives mainly from leakage of electrons from the respiratory chain and, among others, can target mitochondria with detrimental effects 4243. Chronologically aging mpc1 ∆ cells had a higher ROS content, measured as the superoxide-driven conversion of non-fluorescent dihydroethidium (DHE) into fluorescent ethidium (Eth), compared with that of the wt cells (Fig.…”

Evidence for the hallmarks of human aging in replicatively aging yeast

“…Although once thought to be purely detrimental, we now know that low levels of ROS may induce a protective homeostatic response, while only higher levels, which may increase for a variety of reasons, accelerate aging 1. Many other changes have been proposed to contribute to aging related mitochondrial dysfunction, such as an accumulation of mutations and deletions in mtDNA, the oxidation and destabilization of mitochondrial protein complexes, a reduced biosynthesis of iron-sulfur clusters, a decline in the levels of mitochondrial biogenesis, an imbalance of fission and fusion events, and a diminishing quality control from mitophagy 8990. The long list of factors that are thought to contribute to increased damage and decreased turnover for mitochondria have been speculated to influence the natural aging process 1, and mitochondrial dysfunction has therefore been deemed a hallmark of aging.…”