Mitohormesis

Abstract

Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.

Figure 1:

Mitochondrial stress can activate the integrated stress response (ISR) through a DELE1-dependent pathway. Various perturbations in mitochondrial function lead to activation of the OMA1 protease. This mitochondrial enyzme catalyzes the cleaveage of DELE1, resulting in a smaller cytosolic form of the protein (DELE1-S) that can bind and activate HRI. Activation of HRI results in the induction of the ISR, leading to ATF4 induction and the transcription of metabolic genes, and other downstream targets. Other stresses, like low iron levels or impaired translocation, can lead to the accumulation of full length DELE1 (DELE1-L) in the cytosol or on the outer mitochondrial membrane which can also activate HRI.

Figure 2:

Impaired mitochondrial protein import results in the induction of a coordinated mitoprotein-induced stress response. In yeast, accumulation of proteins with a mitochondrial targeting sequence (MTS) in the cytosol leads to (a)mPOS and (b)mitoStore, while impaired mitochondrial translocation leads to (c)mitoTAD, (d)mitoCPR and (f)mitoRQC. These pathways facilitate the ubiquitination (Ub) of stalled proteins, or, (e) the resortment of mistargeted TA proteins to the ER, with subsequent degradation by the proteasome. The orchestration of this response depends, in part, on the sequentional activation of the transcription factors HSF-1, RPN4 and PRD3.

Figure 3:

A variety of nuclear-encoded and mitochondrial-encoded mitokines exist. Mitochondrial stress triggers the ISR/ATF4 dependent induction of GDF15 and FGF21. Similarly, exercise and other factors induce expression of various mitochondrial-derived peptides. Together, these secreted factors coordinate a systemic response to local changes in mitochondrial function.

Figure 4:

Mitohormetic responses are involved in the initiation, progression or response to treatment in a wide array of disease processes. See text for details.