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.