Expression of the RCAN1 gene can be induced by multiple stresses. RCAN1 proteins have both protective and harmful effects, and are implicated in common human pathologies. The mechanisms by which RCAN1s function, however, remain poorly understood. We identify RCAN1s as regulators of mitochondrial autophagy (mitophagy), and demonstrate that induction of RCAN1-1L can cause dramatic degradation of mitochondria. The mechanisms of such degradation involve the adenine nucleotide translocator (ANT) and mitochondrial permeability transition pore (mtPTP) opening. We also demonstrate that RCAN1-1L induction can shift cellular bioenergetics from aerobic respiration to glycolysis, yet RCAN1-1L has very little effect on cell division while it has a cumulative negative effect on cell survival. These results shed the light on mechanisms by which RCAN1s can protect or harm cells, and by which they may operate in human pathologies. They also suggest that RCAN1s are important players in autophagy and such elusive phenomena as mtPTP.

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