Role of the Mitophagy Protein PINK1 in Hypothalamic Neurons: Regulation of Energy Balance and Glucose Homeostasis
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2024
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Abstract
The mediobasal hypothalamus (MBH), particularly the arcuate nucleus (ARC), is a brain region essential for regulating energy balance, glucose metabolism, and feeding behavior. Hypothalamic neurons adapt to different metabolic challenges, such as fasting or high-fat diet (HFD) consumption, to maintain energy homeostasis. Mitochondria contribute to this process by undergoing reshaping, rebuilding, and recycling— processes that together are known as mitochondrial dynamics. Mitophagy, the process of recycling mitochondria through autophagy, ensures the selective removal of damaged mitochondria, maintaining mitochondrial and cellular function under basal metabolic conditions or during metabolic stress. Despite its importance in mitochondrial and cellular function, the function of mitophagy in hypothalamic neurons and their role in regulating energy balance remains poorly understood. This thesis aimed to elucidate the role of mitophagy in hypothalamic neurons, focusing on its impact during fasting and HFD-induced obesity. We observed that both fasting and HFD altered mitophagy-related genes and protein levels in the MBH. Notably, the mRNA levels of the mitophagy protein PINK1, the main regulator of mitophagy, were lower in HFD mice compared to control mice, correlating with impaired fasting-induced food intake. To further explore this, we downregulated PINK1 in AgRP and POMC neurons. PINK1 knockdown in AgRP neurons, but not in POMC neurons, increased body weight, impaired glucose metabolism, and altered adiposity despite no changes in basal or fasting-induced food intake. Experiments in a hypothalamic neuronal cell line revealed that PINK1 is essential for starvation-induced mitophagy. Collectively, these findings show that PINK1 is necessary for maintaining hypothalamic neuronal function and metabolic homeostasis.
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Tesis (Doctor in Biological Sciences with a mention in Physiology)--Pontificia Universidad Católica de Chile, 2024