Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release

Mitophagy is an excellent example of selective autophagy that eliminates damaged or dysfunctional mitochondria, and it is crucial for the maintenance of mitochondrial integrity and function. The critical roles of autophagy in pancreatic β-cell structure and function have been clearly shown. Furthermore, morphological abnormalities and decreased function of mitochondria have been observed in autophagy-deficient β-cells, suggesting the importance of β-cell mitophagy. However, the role of authentic mitophagy in β-cell function has not been clearly demonstrated, as mice with pancreatic β-cell-specific disruption of Parkin , one of the most important players in mitophagy, did not exhibit apparent abnormalities in β-cell function or glucose homeostasis. Instead, the role of mitophagy in pancreatic β-cells has been investigated using β-cell-specific Tfeb -knockout mice ( Tfeb Δβ-cell mice); Tfeb is a master regulator of lysosomal biogenesis or autophagy gene expression and participates in mitophagy. Tfeb Δβ-cell mice were unable to adaptively increase mitophagy or mitochondrial complex activity in response to high-fat diet (HFD)-induced metabolic stress. Consequently, Tfeb Δβ-cell mice exhibited impaired β-cell responses and further exacerbated metabolic deterioration after HFD feeding. TFEB was activated by mitochondrial or metabolic stress-induced lysosomal Ca 2+ release, which led to calcineurin activation and mitophagy. After lysosomal Ca 2+ release, depleted lysosomal Ca 2+ stores were replenished by ER Ca 2+ through ER→lysosomal Ca 2+ refilling, which supplemented the low lysosomal Ca 2+ capacity. The importance of mitophagy in β-cell function was also demonstrated in mice that developed β-cell dysfunction and glucose intolerance after treatment with a calcineurin inhibitor that hampered TFEB activation and mitophagy. Diabetes: Quality control of pancreatic mitochondria is critical A mechanism for eliminating damaged mitochondria in insulin-producing pancreatic beta cells provides an important safeguard against the onset of metabolic dysfunction and diabetes. Researchers have long suspected that this process, known as mitophagy, is essential to ß-cell survival and function, but past studies have yielded conflicting results. Myung-Shik Lee of Soonchunhyang University, Cheonan, South Korea, and colleagues have reviewed current knowledge about how mitophagy is regulated, focusing on a protein called TFEB, a master regulator of mitophagy. Rodent models in which