Metabolism of Hyperpolarized C-acetoacetate to β-hydroxybutyrate Detects Real-time Mitochondrial Redox State and Dysfunction in Heart Tissue

Overview

Journal NMR Biomed

Publisher Wiley

Date 2019 Apr 11

PMID 30968985

Citations 10

Authors

Wei Chen

Gaurav Sharma

Weina Jiang

Nesmine R Maptue

Craig R Malloy

A Dean Sherry

Chalermchai Khemtong

Affiliations

Soon will be listed here.

Abstract

Mitochondrial dysfunction is considered to be an important component of many metabolic diseases yet there is no reliable imaging biomarker for monitoring mitochondrial damage in vivo. A large prior literature on inter-conversion of β-hydroxybutyrate and acetoacetate indicates that the process is mitochondrial and that the ratio reflects a specifically mitochondrial redox state. Therefore, the conversion of [1,3- C]acetoacetate to [1,3- C]β-hydroxybutyrate is expected to be sensitive to the abnormal redox state present in dysfunctional mitochondria. In this study, we examined the conversion of hyperpolarized (HP) C-acetoacetate (AcAc) to C-β-hydroxybutyrate (β-HB) as a potential imaging biomarker for mitochondrial redox and dysfunction in perfused rat hearts. Conversion of HP-AcAc to β-HB was investigated using C magnetic resonance spectroscopy in Langendorff-perfused rat hearts in four groups: control, global ischemic reperfusion, low-flow ischemic, and rotenone (mitochondrial complex-I inhibitor)-treated hearts. We observed that more β-HB was produced from AcAc in ischemic hearts and the hearts exposed to complex I inhibitor rotenone compared with controls, consistent with the accumulation of excess mitochondrial NADH. The increase in β-HB, as detected by C MRS, was validated by a direct measure of tissue β-HB by H nuclear magnetic resonance in tissue extracts. The redox ratio, NAD /NADH, measured by enzyme assays of homogenized tissue, also paralleled production of β-HB from AcAc. Transmission electron microscopy of tissues provided direct evidence for abnormal mitochondrial structure in each ischemic tissue model. The results suggest that conversion of HP-AcAc to HP-β-HB detected by C-MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.

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