Altered Mitochondrial Calcium Metabolism is a Major Factor in Inflammaging
Researchers here report that an overlooked aspect of mitochondrial dysfunction with age, the ability of these organelles to take up calcium ions, provides an important contribution to age-related chronic inflammation when it occurs in the innate immune cells known as macrophages. With advancing age, the immune system falls into a harmful state of overactivation, often referred to as inflammaging. A range of different mechanisms have been shown to contribute to imflammaging, such as the pro-inflammatory secretions of senescent cells, persistent viral infection, mislocated mitochondrial DNA, excess visceral fat tissue, and so forth. Altered mitochondrial calcium metabolism makes an interesting addition to the list; it remains to be seen as to how this issue might be best targeted for therapy.
In this study, we report a surprising discovery that mitochondrial Ca2+ (mCa2+) uptake capacity in macrophages drops significantly with age. This amplifies cytosolic Ca2+ (cCa2+) signaling and promotes NF-κB activation, rendering the macrophages prone to chronic low-grade inflammatory output at baseline and hyper-inflammatory when stimulated. Although mitochondrial dysfunction has long been a suspected driver of aging, our study pinpoints the mitochondrial calcium uniporter (MCU) complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to macrophage-mediated inflammation.
Both chronic low-grade inflammation and mitochondrial dysfunction are known hallmarks of aging, but mechanistic links between these two processes have not been defined with clear links to human biology. For example, defective mitophagy in Prkn-/- mice may contribute to inflammaging by shedding mitochondrial DNA as an inflammatory stimulus in senescent cells. Although a progressive age-associated decline in mitophagy is not evident in human myeloid cells, if one supposes that there is a steady age-associated shedding of inflammatory mediators from other senescent cells, our findings predict that the decreased mCa2+-uptake capacity will render the macrophages hyper-responsive to such inflammatory stimuli from senescent cells and thereby drive inflammaging.
A recent study performed a comprehensive analysis of mitochondrial phenotypes in purified human cell types and mixtures but omitted mCa2+ uptake as a marker of mitochondrial fitness. Interestingly, the authors found that their mitochondrial health index was most impaired in monocytes isolated from aged human donors. Although we chose to focus on macrophage-mediated inflammation, the broad outlines of the mechanistic model are likely applicable to other myeloid cells such as neutrophils and mast cells too, and that is an important line for our future investigations.
Taurine can help regulate calcium levels in mitochondria by interacting with the mitochondrial calcium uniporter (MCU) protein. It is suggested that taurine can modulate the activity of MCU, enhancing its function and promoting the uptake of calcium ions into the mitochondria. By maintaining proper calcium homeostasis, taurine contributes to the overall health and function of the mitochondria.
It probably does not help much if stronger calcium regulators are out of whack, though.
Several hormones play a role in regulating calcium ion uptake by mitochondria. Some of the key hormones that can influence mitochondrial calcium handling include:
Parathyroid Hormone (PTH): PTH increases calcium levels in the bloodstream, which indirectly affects calcium flux into the mitochondria.
Calcitonin: Calcitonin decreases blood calcium levels, potentially affecting mitochondrial calcium uptake.
Thyroid Hormones (T3 and T4): Thyroid hormones can influence mitochondrial function, including calcium handling.
Insulin: Insulin has been implicated in regulating mitochondrial calcium homeostasis in certain tissues.
Glucagon: Glucagon can also have an impact on mitochondrial calcium levels.
Cortisol: Cortisol, a stress hormone, may affect mitochondrial function and calcium handling.
ER-MITOCHONDRIAL COMMUNICATION VIA CALCIUM REGULATES LIFESPAN
In Caenorhabditis elegans, inhibition of the conserved unfolded protein response of the endoplasmic reticulum (ER) (UPR ER) mediator, activating transcription factor (atf)-6, increases lifespan by modulating calcium homeostasis and signaling to mitochondria. Atf-6 loss confers longevity via downregulation of the ER calcium buffer, calreticulin. Endoplasmic reticulum (ER) calcium release via the inositol triphosphate receptor (IP3R/itr-1) is required for longevity, while IP3R/itr-1 gain of function is sufficient to extend lifespan.
Highlighting coordination between organelles, the mitochondrial calcium import channel mcu-1 is also required for atf-6 longevity. IP3R inhibition leads to impaired mitochondrial bioenergetics and hyperfusion, which is sufficient to suppress long life in atf-6 mutants.
This study reveals the importance of organellar calcium handling as a critical output for the UPRER in determining the quality of aging.
• Loss of the UPRER mediator ATF-6 in C. elegans extends lifespan
• ATF-6 loss reverses age-associated increases in calreticulin, an ER calcium sink
• ER calcium efflux via the inositol triphosphate receptor (InsP3R) is required to extend lifespan
• ER calcium release enhances mitochondrial dynamics and bioenergetics
See: Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis https://doi.org/10.1016/j.celrep.2020.108125.
Mitochondria and the ER could regulate each other via Mitochondria-associated endoplasmic reticulum membranes (MAMs)..MAMs-related diseases include hypertension, diabetes, atherosclerosis, and neurodegenerative diseases. More and more studies have shown that the S-palmitoylation of proteins controls the formation of MAMs. The inhibitors of protein acylation, cerulenin and tunicamycin, increase voltage-dependent Ca2+ currents and were proposed as potential drug compounds targeting S-palmitoylation.
See: Control of mitochondria-associated endoplasmic reticulum membranes by protein S-palmitoylation: Novel therapeutic targets for neurodegenerative diseases
https://doi.org/10.1016/j.arr.2023.101920