Mitochondrial stress and mitokines in aging

Abstract

Mitokines are signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues. Among those molecules are FGF21, GDF15 (both expressed in the nucleus) and several mitochondrial-derived peptides, including humanin. Their responsiveness to mitochondrial stress induces mitokine-signaling in response for example to exercise, following mitochondrial challenges in skeletal muscle. Such signaling is emerging as an important mediator of exercise-derived and dietary strategy-related molecular and systemic health benefits, including healthy aging. A compensatory increase in mitokine synthesis and secretion could preserve mitochondrial function and overall cellular vitality. Conversely, resistance against mitokine actions may also develop. Alterations of mitokine-levels, and therefore of mitokine-related inter-tissue cross talk, are associated with general aging processes and could influence the development of age-related chronic metabolic, cardiovascular and neurological diseases; whether these changes contribute to aging or represent "rescue factors" remains to be conclusively shown. The aim of the present review is to summarize the expanding knowledge on mitokines, the potential to modulate them by lifestyle and their involvement in aging and age-related diseases. We highlight the importance of well-balanced mitokine-levels, the preventive and therapeutic properties of maintaining mitokine homeostasis and sensitivity of mitokine signaling but also the risks arising from the dysregulation of mitokines. While reduced mitokine levels may impair inter-organ crosstalk, also excessive mitokine concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure. Preservation of healthy mitokine signaling levels can be achieved by regular exercise and is associated with an increased lifespan.

Keywords: FGF21; GDF15; humanin; mitochondria-derived peptides; mitochondrial stress response; mitohormesis; mitokines.

FIGURE 1

The biphasic response to mitochondrial stress. (a) Mild mitochondrial stress in a healthy organ and organisms with sufficient adaptive capacities will lead to beneficial adaptations both on the cellular and systemic level. (b) Conversely, severe mitochondrial stress or a compromised adaptation capacity may result in the production and release of excessive ROS, mitochondrial damage associated molecular patterns (DAMPs) and reduced levels of energy, leading to permanent cellular and tissue damage

FIGURE 2

Mitochondrial communication of mitochondrial stress. (a) Various molecular stressors in response to systemic or cellular/cell environmental cues can trigger the mitochondrial stress response, which is transmitted via various communication channels. The stress responses can be communicated to other mitochondria (b), other organelles within the cell (c), to other cells (d) or to distant tissues (e). While moderate mitochondrial stress can lead to beneficial adaptations, severe mitochondrial stress or a compromised adaptation capacity may result in the production and release of excessive ROSs, mitochondrial DAMPs, inflammation, reduced levels of energy and ultimately to permanent cellular and tissue damage