Mitochondrial calcium and ROS: present understanding and future directions.

This mini-review and perspective article goes over a brief history of mitochondria and their role in calcium overload and oxidative stress. Altogether, oxidative stress, calcium overload, and mitochondrial dysfunction form a pathophysiological triad, and most of the explanatory power of this triad relies on invoking the mitochondrial permeability transition pore (mPTP) as driving the pathophysiology. As such, many studies claim that calcium overload triggers oxidative stress and acts as the upstream event in mitochondrial dysfunction to explain experimental results. However, recent findings shed new light on this triad and how it affects living tissue. While the mPTP hypothesis has dominated curated explanations, emerging functional and structural data supports a distinct stable overloaded state that better accounts for graded dysfunction in the presence of low intensity chronic oxidative stress. In this stable calcium overload state, mitochondrial dysfunction is evident from the reduced oxidative metabolism impairments accompanying suppressed free radical emission rates, distinct from the effects of opening the mPTP. This refined framework has direct implications for SR/ER-mitochondrial crosstalk in disease and tunes mechanistic models that better align with the available data. While mitochondria absolutely play an important role in various pathologies, they primarily respond to exogenous driving forces that move them into compromised functional states, which in turn amplify cellular disorder. Ideally, this perspective will help refine the intriguing and complex aspects of mitochondrial function in cell death and disease.