Systemic effects of mitochondrial stress

Abstract

Multicellular organisms are complex biological systems, composed of specialized tissues that require coordination of the metabolic and fitness state of each component. In the cells composing the tissues, one central organelle is the mitochondrion, a compartment essential for many energetic and fundamental biological processes. Beyond serving these functions, mitochondria have emerged as signaling hubs in biological systems, capable of inducing changes to the cell they are in, to cells in distal tissues through secreted factors, and to overall animal physiology. Here, we describe our current understanding of these communication mechanisms in the context of mitochondrial stress. We focus on cellular mechanisms that deal with perturbations to the mitochondrial proteome and outline recent advances in understanding how local perturbations can affect distal tissues and animal physiology in model organisms. Finally, we discuss recent findings of these responses associated with metabolic and age-associated diseases in mammalian systems, and how they may be employed as diagnostic and therapeutic tools.

Keywords: aging; mitochondria; stress.

Figure 1. Pathways protecting mitochondria

Several cellular pathways may be employed to protect mitochondria against stress, protecting the organelle at different levels. See text for details.

Figure 2. Cell non‐autonomous regulation of mitochondrial stress in Caenorhabditis elegans

The communication between the nervous system and the periphery, and the genetic components important for this communication in C. elegans, are shown.

Figure 3. Cell non‐autonomous regulation of mitochondrial stress in mammals

(A) The signaling tissues, the mitokines, and the effects on the receiving tissues are noted. (B) The age‐associated change in mitochondrial phenotypes, and the levels of different mitochondrially associated proteins, is shown.

Figure 4. The temporal order for the mitochondrial stress response on the transcriptional level in a mitochondrial disease model (as defined in ref. 130)

Note that in human proliferating cells, ATF4 induction precedes the 1^st stage of ISRmt (I). In post‐mitotic cells, the induction of ATF3 and ATF4 was dependent on FGF21 (II), so that induction of ATF4 does not precede 1^st stage ISRmt in this model. ATF5 induction is independent of ATF4. Of note, in a separate study 46, a reduction in mitochondrial ribosomal proteins, and a decrease in mitochondrial translation, in response to mitochondrial stress in HeLa cells, was also described.