Dataset Information

Endoplasmic Reticulum Stress-mediated Mitochondrial Dysfunction in Aged Hearts

ABSTRACT: Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 mo. mice that manifest mitochondrial dysfunction. OXPHOS was decreased in 24 mo. IFM oxidizing complex I and complex IV substrates. Proteomic analysis showed that the content of multiple complex I subunits was decreased in IFM from 24 mo. hearts, but remained unchanged in in 18 mo. IFM without a decrease in OXPHOS. Feeding mice with 4-phenylbutyrate (4-PBA) for two weeks attenuated the ER stress and improved mitochondrial function in 24 mo. mice. These results indicate that ER stress contributes to the mitochondrial dysfunction in aged hearts. Attenuation of ER stress is a potential approach to improve mitochondrial function in aged hearts.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Ling Li

LAB HEAD: Edward Lesnefsky

PROVIDER: PXD018545 | Pride | 2020-07-23

REPOSITORIES: Pride

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Publications

Endoplasmic reticulum stress-mediated mitochondrial dysfunction in aged hearts.

Chen Qun Q Samidurai Arun A Thompson Jeremy J Hu Ying Y Das Anindita A Willard Belinda B Lesnefsky Edward J EJ

Biochimica et biophysica acta. Molecular basis of disease 20200719 11

Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 m ...[more]

PMID: 32698045

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Project description:SEPN1 is a type II protein of the endoplasmic reticulum (ER) whose loss of function gives rise to a collection of debilitating autosomal recessive myopathies gathered under the umbrella term of SEPN1-related myopathy (RM). At the moment, SEPN1-RM lacks an effective pharmacological treatment; thus, the medical management of the disease is only supportive. The potentially fatal diaphragmatic weakness leading to respiratory insufficiency in patients still ambulant is the main reason for medical concerns. Thus, studies on SEPN1-RM pathogenesis are necessary to implement a targeted pharmacological therapy aimed at relieving the general muscle weakness and the more worrisome diaphragmatic dysfunction. Here, we show a physical and functional interaction between SEPN1 and the ER stress mediator ERO1 alpha (henceforth, ERO1). Both SEPN1 and ERO1 are involved in the redox regulation of proteins into the ER, although in an opposite way SEPN1 imposes a less oxidant ER poise while ERO1 a more oxidant one, conceivable with a reductase function of SEPN1 and an oxidase one of ERO1. Furthermore, both are mainly localized in a region of the ER in close contact with mitochondria termed mitochondria-associated membranes (MAMs) and their loss impacts oppositely on the short-range MAMs, thereby impinging ER-mitochondria Ca2+ dynamics, OXPHOS, and bioenergetics. We find that ERO1 depletion restores the impaired short-range MAMs due to SEPN1 loss together with mitochondrial ATP. ERO1 knockout in a mouse background of SEPN1 loss blunts ER stress and the consequent Unfolded Protein Response (UPR) while it rescues the diaphragmatic weakness by improving ER/mitochondria contacts, calcium dynamics, and OXPHOS. Importantly, treatments of SEPN1 knock out mice with the chemical chaperone tauroursodeoxycholic acid (TUDCA) mimic the results of ERO1 loss improving calcium dynamics, OXPHOS, ER/mitochondria contacts, thereby rescuing diaphragmatic weakness as well. In addition, TUDCA-treated SEPN1-RM patients-derived myoblasts show a dynamic dose-dependent increase in ATP levels under ER stress conditions suggesting improved mitochondrial function. Thus, our findings point to the ERO1 axis in the pathogenesis of SEPN1-RM thereby impinging on MAMs and mitochondria bioenergetics and recall for the efficacy of a pharmacology therapy with ad hoc ER stress/ERO1 inhibitors for SEPN1-RM.

Project description:Background: Inhibitors of sodium glucose linked transporter 2 (SGLT2i) improve heart failure (HF) outcomes in patients independent of diabetes. While animal studies suggest SGLT2i improve cardiac metabolism, the effect of SGLT2i on mitochondrial function in the heart is not known. Our goal was to assess the effects of SGLT2i on mitochondrial function, high energy phosphates and genes encoding mitochondrial proteins in hearts of mice with and without diet-induced diabetes. Methods & Results: Ertugliflozin (Ertu; formulated to 0.5 mg/g of diet) was given for 4 months to mice fed a high fat, high sucrose (HFHS) diet that causes diabetic cardiomyopathy or control diet (CD). Mitochondrial function was measured in isolated cardiac mitochondria. Myocardial energetics were assessed by NMR spectroscopy simultaneously with systolic function in isolated beating hearts. Myocardial gene expression was assessed by RNA seq using gene set enrichment analysis. HFHS diet caused myocardial hypertrophy and diastolic dysfunction, mitochondrial dysfunction (decreased ATP production, increased reactive oxygen species release) and an impaired energetic response to increased work demand - all of which were prevented by Ertu. Conctractile function, as reflected by the rate x pressure product (RPP), was super-normalized to a value 124% of CD hearts at high work demand. In control mice, Ertu had no effect on isolated mitochondria function or high energy phosphates, but similar to HFHS hearts, caused super-normalization of RPP to 125% of CD hearts. By GSEA the highest scoring gene set for Ertu treatment was oxidative phosphorylation (OXPHOS), which was up-regulated across all groups while controlling for diet with a Normalized Enrichment Score (NES) of +3.71, and was similarly up-regulated in HFHS-fed mice (NES, +3.32) and in CD-fed mice (NES, +3.34). Fatty acid metabolism (FAM) was the second-highest scoring gene set for Ertu, and, like OXPHOS, was up-regulated independent of diet (NES, +2.82). Conclusion: The super-normalization of contractile function and induction of the OXPHOS and FAM gene sets by Ertu are independent of diabetic status. Pro-metabolic remodeling of the myocardium by Ertu may support increased contractile function and contribute to the beneficial actions of Ertu in states such as heart failure that are associated with impaired cardiac mitochondrial function.

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Dataset Information

Endoplasmic Reticulum Stress-mediated Mitochondrial Dysfunction in Aged Hearts

Publications

Endoplasmic reticulum stress-mediated mitochondrial dysfunction in aged hearts.

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