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Mutations of mitochondrial DNA – cause or consequence of the ageing process?

Mutationen der mitochondrialen DNA – Grund oder Folge des Alterungsprozesses

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Abstract

Ageing is a stochastic process which leads to a gradual decline in cellular, tissue and even organ function, especially in energy dependent postmitotic tissues like skeletal muscle, brain and heart. The mitochondrial theory of ageing is based on the assumption that reactive oxygen species (ROS) and free radicals generated in the immediate vicinity of the electron transport chain during the lifespan of an organism damage proteins, lipids and mitochondrial DNA (mtDNA). Whereas it was generally believed that mitochondria are among the important players regarding the ageing process, two recent important approaches shed new light on the complex interactions. It has been shown by single cell experiments and computer simulation models that mitochondrial mutations are generated stochastically in childhood or early adolescence and accumulate clonally in a cell or muscle fibre, leading to a local age related impairment of cellular energy supply. Other important observations come from mitochondrial mutator mice, harbouring mitochondrial mutations due to a deficient repair enzyme (POLG). These mice reveal a premature senescence but do not exhibit a vicious cycle of increased oxidative damage or ROS production as has been postulated by the mitochondrial theory of ageing. At the moment it is hard to decide, if mitochondrial mutations are the cause or consequence of human ageing, but it is suggested that mitochondrial point mutations are just the consequence, while deletions seem to play a causal role.

Zusammenfassung

Der Alterungsprozess führt zu einer durch zufällige Ereignisse beeinflussten steten Abnahme der Zell-, Gewebe und Organfunktion und betrifft besonders energieabhängige postmitotische Gewebe wie Skelettmuskel, Gehirn und Herz. Die mitochondriale Alterungstheorie fußt auf der Annahme, das reaktive Sauerstoffverbindungen und freie Radikale, die in der unmittelbaren Umgebung der Atmungskette während des Lebens eines Organismus in den Mitochondrien gebildet werden, Proteine, Lipide und die mitochondriale DNA (mtDNA) schädigen. Während man lange glaubte, dass den Mitochondrien eine entscheidende Bedeutung im Alterungsprozess zukommt, haben zwei neuere experimentelle Ansätze neues Licht in das Dunkel gebracht. Durch Einzelzellexperimente und mathematische Modelle konnte gezeigt werden, dass mitochondriale Mutationen zufällig bereits im Kindesalter oder bei Heranwachsenden entstehen, klonal in einer Zelle oder Muskelfaser vermehrt werden und zu einer altersabhängigen Beeinträchtigung der lokalen zellulären Energieversorgung führen. Weitere wichtigeBeobachtungen erfolgten bei so genannten Mutator-Mäusen, bei denen mitochondriale Mutationen viel häufiger auftreten, da ein Reperaturenzym (POLG) defekt ist. Während diese Mäuse zwar das Bild einer deutlichen Voralterung zeigen, findet sich kein erhöhter oxidativer Stress oder eine verstärkte ROS-Produktion wie nach der mitochondrialen Alterungstheorie zu erwarten wäre. Momentan lässt sich noch nicht entscheiden, ob die mitochondrialen DNA-Mutationen Grund oder Folge des menschlichen Alterungsprozesses sind, aber es scheint so zu sein, dass Punktmutationen nur die Folge sind, während Deletionen eher eine kausale Rolle zukommt.

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  1. Department of Forensic Medicine, University Hospital of Schleswig-Holstein, Kahlhorststraße 31–35, 23562, Lübeck, Germany

    C. Meissner

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Meissner, C. Mutations of mitochondrial DNA – cause or consequence of the ageing process?. Z Gerontol Geriat 40, 325–333 (2007). https://doi.org/10.1007/s00391-007-0481-z

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