Endosomal v-ATPase as a Sensor Determining Myocardial Substrate Preference

Abstract

The heart is a metabolically flexible omnivore that can utilize a variety of substrates for energy provision. To fulfill cardiac energy requirements, the healthy adult heart mainly uses long-chain fatty acids and glucose in a balanced manner, but when exposed to physiological or pathological stimuli, it can switch its substrate preference to alternative substrates such as amino acids (AAs) and ketone bodies. Using the failing heart as an example, upon stress, the fatty acid/glucose substrate balance is upset, resulting in an over-reliance on either fatty acids or glucose. A chronic fuel shift towards a single type of substrate is linked with cardiac dysfunction. Re-balancing myocardial substrate preference is suggested as an effective strategy to rescue the failing heart. In the last decade, we revealed that vacuolar-type H+-ATPase (v-ATPase) functions as a key regulator of myocardial substrate preference and, therefore, as a novel potential treatment approach for the failing heart. Fatty acids, glucose, and AAs selectively influence the assembly state of v-ATPase resulting in modulation of its proton-pumping activity. In this review, we summarize these novel insights on v-ATPase as an integrator of nutritional information. We also describe its exploitation as a therapeutic target with focus on supplementation of AA as a nutraceutical approach to fight lipid-induced insulin resistance and contractile dysfunction of the heart.

CD36 as a gatekeeper of myocardial lipid metabolism and therapeutic target for metabolic disease

“…Only the assembled state of v-ATPase is compatible with optimal proton pump activity, whereas release of the V 1 complex into the cytoplasm leads to inhibition of proton pumping activity. A number of substrates and metabolites have been found to regulate the v-ATPase assembly state, and the list is still growing (160). The most relevant ones in the context of this review are glucose and fatty acids, which have opposing effects: increased glucose supply favors v-ATPase assembly and CD36 retention, whereas elevated fatty acid levels induce disassembly and CD36 release from endosomes (160).…”

Differential intracellular management of fatty acids impacts on metabolic stress-stimulated glucose uptake in cardiomyocytes

“…Extracellular lipids may interact with glucose uptake regulation by inducing disassembly and inhibition of the vacuolar-type H + -ATPase (v-ATPase) 31 . This results in further stimulation of FA uptake and inhibition of insulin-stimulated GLUT4 translocation both in cultured cardiomyocytes and in ex vivo cardiomyocytes obtained from rats fed a high-fat diet 31 , 32 . Although LD biogenesis could prevent v-ATPase by sequestering intracellular FA, we do not think that this mechanism is involved in the protective effect of LD on metabolic stress-stimulated glucose uptake for two reasons.…”

Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit

“…V-ATPase is highly conserved and expressed in virtually all eukaryotes as a multi-subunit complex, composed of a transmembrane V o domain (subunits a, c, c', c'', d, e) that transports H + across membrane, and a cytosolic V 1 domain (subunits A-H) responsible for ATP hydrolysis. V-ATPase regulates the pH of intracellular vesicles, such as endosomes, lysosomes and Golgi apparatus 13 - 16 , playing critical roles in receptor-mediated signaling, vesicle trafficking, receptor recycling, protein degradation and ion homeostasis 17 - 19 . Beyond pumping protons across membranes, V-ATPase also acts as a central hub for monitoring and responding to changes in cellular nutrient levels and energy status by modulating the activity of mammalian target of rapamycin complex 1 and AMP activated kinase 20 , 21 .…”

“…V-ATPase regulates the pH of intracellular vesicles, such as endosomes, lysosomes and Golgi apparatus [13][14][15][16], playing critical roles in receptor-mediated signaling, vesicle trafficking, receptor recycling, protein degradation and ion homeostasis [17][18][19]. Beyond pumping protons across membranes, V-ATPase also acts as a central hub for monitoring and responding to changes in cellular nutrient levels and energy status by modulating the activity of mammalian target of rapamycin complex 1 and AMP activated kinase [20,21].…”