Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration

Simple Summary This review will comprise an overview of insulin and its history, structure, synthesis, secretion, signaling, and peripheral and brain roles. Further, the impact that metabolic diseases and the insulin resistance (IR) condition can exert on brain function will be surveyed. Later, attention will be given to the complex relation of mitochondrial dysfunction, brain insulin resistance, and neurodegenerative disease, especially Alzheimer's disease (AD). We will also focus our consideration on the role played by insulin or the IR condition in mitochondrial homeostasis by analyzing the different processes involved in the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), as well as pathophysiological implications of these aspects. Finally, the possibility of employing the mitochondrion as a target to fight dysmetabolism and AD-related effects will also be reviewed. Insulin was discovered and isolated from the beta cells of pancreatic islets of dogs and is associated with the regulation of peripheral glucose homeostasis. Insulin produced in the brain is related to synaptic plasticity and memory. Defective insulin signaling plays a role in brain dysfunction, such as neurodegenerative disease. Growing evidence suggests a link between metabolic disorders, such as diabetes and obesity, and neurodegenerative diseases, especially Alzheimer's disease (AD). This association is due to a common state of insulin resistance (IR) and mitochondrial dysfunction. This review takes a journey into the past to summarize what was known about the physiological and pathological role of insulin in peripheral tissues and the brain. Then, it will land in the present to analyze the insulin role on mitochondrial health and the effects on insulin resistance and neurodegenerative diseases that are IR-dependent. Specifically, we will focus our attention on the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), in healthy and altered cases. Finally, this review will be projected toward the future by examining the most promising treatments that target the mitochondria to cure neurodegenerative diseases associated with metabolic disorders.