Mitochondria and the culture of the Borg: understanding the integration of mitochondrial function within the reticulum, the cell, and the organism

Abstract

As endosymbionts, the mitochondria are unique among organelles. This review provides insights into mitochondrial behavior and introduces the idea of a unified collective, an interconnected reticulum reminiscent of the Borg, a fictional humanoid species from the Star Trek television series whereby decisions are made within their network (or "hive"), linked to signaling cascades that coordinate the cross-talk between mitochondrial and cellular processes ("subspace domain"). Similarly, mitochondrial dynamics are determined by two distinct processes, namely the local regulation of fission/fusion and the global control of their behavior through cellular signaling pathways. Indeed, decisions within the hive provide each mitochondrial unit with autonomous control of their own degradation, whereby mitochondrial fusion is inactivated and they become substrates for autophagy. Decisions within the subspace domain couple signaling pathways involved in the functional integration of mitochondria with complex cellular transitions, including developmental cues, mitosis, and apoptosis.

Figure 1

Controlling the mitochondrial collective. A single COS7 cell is illustrated in the center with the mitochondria labeled using a yellow fluorescent protein (shown in white). The steady state morphology of the mitochondria is continually remodeled based on local decisions within the “hive”. The four images in the left panel illustrate different dynamics, including branching, fission, clustering, fusion, and swelling. Changes in the cellular state, including cell cycle transitions, metabolic changes, stress, or cell death (right panels) lead to the activation of signaling pathways within the “subspace domain” that trigger global changes in the mitochondrial reticulum.

Figure 2

Signaling modules and switches that orchestrate mitochondrial behavior. This figure illustrates some of the complex post-translational modifications discussed within the text. Mitochondrial fission is achieved through the recruitment and oligomerization of the Dynamin Related Protein DRP1. There is evidence that this protein is SUMOylated, phosphorylated, and ubiquitinated, all of which will impact the activity of DRP1 in unique and overlapping ways. Modifying enzymes include MAPL, a SUMO E3 ligase, Protein kinase A, and cyclin B (kinases), and MarchV/Mitol (a ubiquitin E3 ligase). Deconjugating enzymes include SenP5 (a SUMO protease), calcineurin (a phosphatase), and potential deubiquitinating enzymes (DUBs) that have yet to be identified. Phosphorylation by PKA inhibits the recruitment of DRP1, while phosphorylation at a different site by Cyclin B promotes mitochondrial fission during mitosis. Mitochondrial fusion is regulated primarily through the proteolytic cleavage of the intermembrane space GTPase Opa1, and through the regulation of mitofusin (more clearly shown for yeast Fzo1) protein levels by ubiquitination. Mitochondrial fusion is inhibited during cell death and upon loss of electrochemical potential, and is stimulated in mild stress conditions and during G1/S. The combinatorial use of these modifications has not yet been tested directly in experimental models and there is much more to be discovered.