Mitochondria: An Integrative Hub Coordinating Circadian Rhythms, Metabolism, the Microbiome, and Immunity

Abstract

There is currently some understanding of the mechanisms that underpin the interactions between circadian rhythmicity and immunity, metabolism and immune response, and circadian rhythmicity and metabolism. In addition, a wealth of studies have led to the conclusion that the commensal microbiota (mainly bacteria) within the intestine contributes to host homeostasis by regulating circadian rhythmicity, metabolism, and the immune system. Experimental studies on how these four biological domains interact with each other have mainly focused on any two of those domains at a time and only occasionally on three. However, a systematic analysis of how these four domains concurrently interact with each other seems to be missing. We have analyzed current evidence that signposts a role for mitochondria as a key hub that supports and integrates activity across all four domains, circadian clocks, metabolic pathways, the intestinal microbiota, and the immune system, coordinating their integration and crosstalk. This work will hopefully provide a new perspective for both hypothesis-building and more systematic experimental approaches.

Keywords: circadian rhythmicity; immune system; intestinal microbiota; metabolism; mitochondria.

FIGURE 1

Mitochondria regulate circadian rhythmicity through NAD⁺ production, SIRT1 and SIRT3 activation, and mitochondrial dynamics. The Sirtuin 1 (SIRT1) and Sirtuin 3 (SIRT3) activity as HDACs is dependent on NAD⁺, and SIRT1 and SIRT3 counteract CLOCK; NAD⁺ synthesis is dependent on circadian rhythmicity, and this is related to mitochondrial dynamics. NAD⁺, Nicotinamide adenin dinucleotide (oxidized); SIRT1, Sirtuin 1; SIRT3, Sirtuin 3; BMAL1, Brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1; CLOCK, circadian locomotor output cycles kaput; RORα, Retinoic acid receptor-related orphan receptor α; REV-ERBα, Reverse strand of ERBA (REV-ERBα is encoded by the opposite DNA strand of the ERBA oncogene, hence its name); NFIL3, nuclear factor interleukin 3; DBP, D-box binding protein; CRY, Cryptochrome; PER, Period; CCG, Clock-Controlled Genes.

FIGURE 2

Glycolysis and Krebs cycle-derived metabolites, as well as microbiota-derived metabolites, exert biological functions beyond energetic and biosynthetic metabolism.

FIGURE 3

Intestinal microbiota-derived short-chain fatty acids, methane, and hydrogen sulfide regulate inflammatory responses. Microbiota-derived products such as SFCAs (mainly acetate, butyrate, and propionate), CH₄, and H₂S can cross the intestinal epithelial cell barrier and interact with the immune system cells, activating G protein-coupled receptors or passing through cell membranes, promoting cell signaling and modulating the immune response.

FIGURE 4

Mitochondria as an integrative hub coordinating circadian rhythms, metabolism, the microbiome, and immunity.