Dataset Information

Augmenting Vacuolar H⁺-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.

ABSTRACT: The diabetic heart is characterized by a shift in substrate utilization from glucose to lipids, which may ultimately lead to contractile dysfunction. This substrate shift is facilitated by increased translocation of lipid transporter CD36 (SR-B2) from endosomes to the sarcolemma resulting in increased lipid uptake. We previously showed that endosomal retention of CD36 is dependent on the proper functioning of vacuolar H⁺-ATPase (v-ATPase). Excess lipids trigger CD36 translocation through inhibition of v-ATPase function. Conversely, in yeast, glucose availability is known to enhance v-ATPase function, allowing us to hypothesize that glucose availability, via v-ATPase, may internalize CD36 and restore contractile function in lipid-overloaded cardiomyocytes. Increased glucose availability was achieved through (a) high glucose (25 mM) addition to the culture medium or (b) adenoviral overexpression of protein kinase-D1 (a kinase mediating GLUT4 translocation). In HL-1 cardiomyocytes, adult rat and human cardiomyocytes cultured under high-lipid conditions, each treatment stimulated v-ATPase re-assembly, endosomal acidification, endosomal CD36 retention and prevented myocellular lipid accumulation. Additionally, these treatments preserved insulin-stimulated GLUT4 translocation and glucose uptake as well as contractile force. The present findings reveal v-ATPase functions as a key regulator of cardiomyocyte substrate preference and as a novel potential treatment approach for the diabetic heart.

SUBMITTER: Wang S

PROVIDER: S-EPMC7073192 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Augmenting Vacuolar H<sup>+</sup>-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.

Wang Shujin S Wong Li-Yen LY Neumann Dietbert D Liu Yilin Y Sun Aomin A Antoons Gudrun G Strzelecka Agnieszka A Glatz Jan F C JFC Nabben Miranda M Luiken Joost J F P JJFP

International journal of molecular sciences 20200223 4

The diabetic heart is characterized by a shift in substrate utilization from glucose to lipids, which may ultimately lead to contractile dysfunction. This substrate shift is facilitated by increased translocation of lipid transporter CD36 (SR-B2) from endosomes to the sarcolemma resulting in increased lipid uptake. We previously showed that endosomal retention of CD36 is dependent on the proper functioning of vacuolar H<sup>+</sup>-ATPase (v-ATPase). Excess lipids trigger CD36 translocation thro ...[more]

PMID: 32102213

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Project description:Kinetoplastid parasites cause lethal diseases in humans and animals. The kinetoplast itself contains the mitochondrial genome, comprising a huge, complex DNA network that is also an important drug target. Isometamidium, for example, is a key veterinary drug that accumulates in the kinetoplast in African trypanosomes. Kinetoplast independence and isometamidium resistance are observed where certain mutations in the F1-γ-subunit of the two-sector F1Fo-ATP synthase allow for Fo-independent generation of a mitochondrial membrane potential. To further explore kinetoplast biology and drug resistance, we screened a genome-scale RNA interference library in African trypanosomes for isometamidium resistance mechanisms. Our screen identified 14 V-ATPase subunits and all 4 adaptin-3 subunits, implicating acidic compartment defects in resistance; V-ATPase acidifies lysosomes and related organelles, whereas adaptin-3 is responsible for trafficking among these organelles. Independent strains with depleted V-ATPase or adaptin-3 subunits were isometamidium resistant, and chemical inhibition of the V-ATPase phenocopied this effect. While drug accumulation in the kinetoplast continued after V-ATPase subunit depletion, acriflavine-induced kinetoplast loss was specifically tolerated in these cells and in cells depleted for adaptin-3 or endoplasmic reticulum membrane complex subunits, also identified in our screen. Consistent with kinetoplast dispensability, V-ATPase defective cells were oligomycin resistant, suggesting ATP synthase uncoupling and bypass of the normal Fo-A6-subunit requirement; this subunit is the only kinetoplast-encoded product ultimately required for viability in bloodstream-form trypanosomes. Thus, we describe 30 genes and 3 protein complexes associated with kinetoplast-dependent growth. Mutations affecting these genes could explain natural cases of dyskinetoplasty and multidrug resistance. Our results also reveal potentially conserved communication between the compartmentalized two-sector rotary ATPases.

Dataset Information

Augmenting Vacuolar H⁺-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.

Publications

Augmenting Vacuolar H<sup>+</sup>-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.

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Dataset Information

Augmenting Vacuolar H+-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.

Publications

Augmenting Vacuolar H<sup>+</sup>-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Augmenting Vacuolar H⁺-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction.