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Abstract

Pancreatic β-cells rely on mitochondria to couple nutrient metabolism to insulin secretion, making them susceptible to metabolic stress. In diabetes, disrupted mitochondrial metabolism, impaired autophagy, and premature β-cell senescence are linked to progressive β-cell dysfunction. The anti-apoptotic protein Bcl-𝚡ʟ contributes to mitochondrial regulation in β-cells, whereas autophagy serves as the primary pathway for mitochondrial turnover. This thesis investigated how these processes interface with mitochondrial quality control to determine β-cell adaptation under glucose stress. Using a β-cell–specific Bcl-𝚡ʟ knockout model, we found that Bcl-𝚡ʟ is required for normal induction and activity of the transcriptional coactivator PGC-1α in response to glucose stress. Impaired PGC-1α function disrupted redox control, leading to elevated mitochondrial ROS and subsequent repression of oxidative-phosphorylation genes and reduced respiratory efficiency in glucose-stressed β-cells. These findings identify a previously unrecognized Bcl-𝚡ʟ–PGC-1α signaling axis that coordinates adaptive retrograde mitochondria-to-nucleus communication. We also found that PGC-1α supports components of the mitochondrial integrated stress response, broadening its known contribution to β-cell stress resilience. In a complementary model of mitochondrial quality-control failure, β-cells lacking the core autophagy gene Atg5 accumulated fragmented, depolarized mitochondria and were sensitized to glucose-stress-induced DNA damage and senescence markers. This represents the first demonstration that autophagy deficiency sensitizes β-cells to senescence-like changes under nutrient stress. Together, these studies identify new mechanisms of β-cell mitochondrial adaptation and reveal the cellular consequences of their failure, highlighting mitochondrial quality control as a central determinant of β-cell resilience and a potential therapeutic target to preserve β-cell function and delay diabetes progression.