Unexpected molecular sexual dimorphisms (in host-microbial interactions).
While wandering through the literature, I found myself reading a paper by departmental colleagues Dong Tian, Mingxue Cui, and Min Han (2024). They describe effects of bacterial mucopolysaccharides, components of bacterial cell walls, on mitochondrial functions in mice and human cells. While an interesting example of the interaction between components of the microbiome and its host, what was particularly surprising to me was their observation that these mucopolysaccharides had sex-specific effects on mitochondrial functions (footnote 1). This sexual dimorphism was documented by examining the generation of reactive oxygen species (ROS) formed during reactions involving molecular oxygen (O2), concentrations of ATP (cells’ primary energy currency), and body weight, when comparing control mice with mice treated with “an antibiotic cocktail to deplete the intestinal microbiota in order to eliminate the source of muropeptides following a well-established protocol for antibiotic-induced microbiome depletion (AIMD)”. One interesting result was that the addition of bacteria-derived proteoglycan derived “muropeptides” (see their figure 3 ↓ (modified) and the included image, derived from it with scale modifications) dramatically inhibited the effects of AIMD treatment on a number of cellular behaviors in mouse and human cells.
Perhaps It should be expected that removing an organism’s internal microbiome causes a number of stress effects on the host, nor that mitochondria (derived, via endosymbiosis and subsequent evolutionary adaptations) respond to such changes. Mitochondrial functions seem particularly sensitive to general cellular stresses (a topic considered in more detail in the appearance of mitochondrial stress effects associated with “knock-out” mutations in a number of intermediate filament proteins (the work of others reviewed here).
What was surprising (certainly to me) was the observation that male and female cells responded differently to muropeptides; something reported previously by Gabanyi et al (2022). There are, of course, a number of possible and plausible reasons for such differences. For one, a recent study of the cellular (gene-protein) network involved in male gamete formation further revealed its evolutionarily ancient origin and its complexity, involving the “expression of approximately 10,000 protein-coding genes, a third of which define a genetic scaffold of deeply conserved genes” (Brattig-Correia et al., 2024). While this study focussed on the male germ lines, the tissue that generates sperm, it is likely that differences in gene expression occur throughout the body. As an example, based on analyses of protein expression in post-mortem human brain tissues Wingo et al (2023) reported that “Among the 1,239 proteins, 51% had higher expression in females and 49% had higher expression in males”.
In this light, It is tempting to speculate that the effects of mucoproteins might well extend beyond the mouse and lead to sex-specific differences in humans as well. The source of these differences could be the result of cellular and tissue specific differences sex-influenced variations in gene expression, protein activity, and cellular organization, including social interactions between cells in tissues and organs. They may arise as indirect (and complex) effects of androgen or estrogen-based hormone responses. It is interesting how these differences may or may not impact a range of physiological effects.
Footnote
Mitochondria are evolutionary derivatives of a bacterial endosymbiont(s) found in eukaryotes (organisms like us). For some background see Mitochondrial activity, embryogenesis, and the dialogue between the big and little brains of the cell.
literature cited:
Brattig-Correia et al., (2024). The conserved genetic program of male germ cells uncovers ancient regulators of human spermatogenesis. eLife, 13, RP95774.
Gabanyi et al.'(2022). Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science 376, eabj3986. .
Tian, D., Cui, M., & Han, M. (2024). Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals. Cell reports, 43(4).
Wingo et al., (2023). Sex differences in brain protein expression and disease. Nature medicine, 29, 2224-2232.
bioliteracy / biofundamentals 