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Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock

by Deborah M Muoio

Abstract: Normal energy metabolism is characterized by periodic shifts in glucose and fat oxidation, as the mitochondrial machinery responsible for carbon combustion switches freely between alternative fuels according to physiological and nutritional circumstances. These transitions in fuel choice are orchestrated by an intricate network of metabolic and cell signaling events that enable exquisite crosstalk and cooperation between competing substrates to maintain energy and glucose homeostasis. By contrast, obesity-related cardiometabolic diseases are increasingly recognized as disorders of metabolic inflexibility, in which nutrient overload and heightened substrate competition result in mitochondrial indecision, impaired fuel switching, and energy dysregulation. This Perspective offers a speculative view on the molecular origins and pathophysiological consequences of metabolic inflexibility.
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Describes the concept of "substrate competition" in the mitochondria, where competing substrates (glucose, fatty acids, amino acids) lead to "indecision" in which of the fuels to burn. Speculates that substrate competition is the root cause of "insulin resistance," that the reason is "too much mixed food all the time," and that restricting at least one macro (e.g. doing keto) might alleviate this issue.

Original source: https://pubmed.ncbi.nlm.nih.gov/25480291/