Aging: All roads lead to mitochondria

Abstract

Mitochondria were described as early as 1890 as ubiquitous intracellular structures by Ernster and Schatz (1981) [1]. Since then, the accretion of knowledge in the past century has revealed much of the molecular details of mitochondria, ranging from mitochondrial origin, structure, metabolism, genetics, and signaling, and their implications in health and disease. We now know that mitochondria are remarkably multifunctional and deeply intertwined with many vital cellular processes. They are quasi-self organelles that still possess remnants of its bacterial ancestry, including an independent genome. The mitochondrial free radical theory of aging (MFRTA), which postulated that aging is a product of oxidative damage to mitochondrial DNA, provided a conceptual framework that put mitochondria on the map of aging research. However, several studies have more recently challenged the general validity of the theory, favoring novel ideas based on emerging evidence to understand how mitochondria contribute to aging and age-related diseases. One prominent topic of investigation lies on the fact that mitochondria are not only production sites for bioenergetics and macromolecules, but also regulatory hubs that communicate and coordinate many vital physiological processes at the cellular and organismal level. The bi-directional communication and coordination between the co-evolved mitochondrial and nuclear genomes is especially interesting in terms of cellular regulation. Mitochondria are dynamic and adaptive, rendering their function sensitive to cellular context. Tissues with high energy demands, such as the brain, seem to be uniquely affected by age-dependent mitochondrial dysfunction, providing a foundation for the development of novel mitochondrial-based therapeutics and diagnostics.

Keywords: Aging; Communication; Genomic instability; Immunity; Inflammation; Longevity; Mitochondria; Mitochondrial-derived peptides; Mitonuclear; Oxidative stress.

Fig. 1.

Mitochondria are multifunctional organelles that are extensively integrated with many cellular activities. The broad actions of mitochondria that are adaptive to cellular contexts render their role in aging highly complex and a moving target. mtDNA mutations and heteroplasmy increase with age, which are strongly implicated in aging phenotypes and age-related diseases. Mitochondria are also heavily involved in immune responses, including mtDNA-induced stimulation of inflammatory pathways. Further, mitochondria are regulatory hubs that communicate and coordinate many vital physiological processes at the cellular (i.e. other subcellular compartments (inter-organelle), including the nucleus(mitonuclear)) and organismal level (i.e. endocrine). Several methods of communication are employed, including proteostasis signaling (i.e. UPR^mt and ISR), mitochondrial metabolites, and mitokines (e.g. mitochondrial-derived peptides (MDPs)). Multiple age-dependent mitochondrial dysfunctions are thought to ultimately cause maladaptive metabolic shifts and reduce organismal fitness, contributing to aging phenotypes and age-related disabilities/diseases.