Metabolism of hyperpolarized 13 C-acetoacetate to β-hydroxybutyrate detects real-time mitochondrial redox state and dysfunction in heart tissue

Wei Chen, Gaurav Sharma, Weina Jiang, Nesmine R. Maptue, Craig R Malloy, Dean Sherry, Chalermchai Khemtong

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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- 13 C]acetoacetate to [1,3- 13 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) 13 C-acetoacetate (AcAc) to 13 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 13 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 13 C MRS, was validated by a direct measure of tissue β-HB by 1 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 13 C-MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.

Original languageEnglish (US)
Article numbere4091
JournalNMR in biomedicine
DOIs
StatePublished - Jan 1 2019

Fingerprint

Hydroxybutyrates
Metabolism
Oxidation-Reduction
Tissue
NAD
Rotenone
Biomarkers
Magnetic Resonance Spectroscopy
Rats
Tissue Extracts
Magnetic resonance spectroscopy
Metabolic Diseases
Imaging techniques
Enzyme Assays
Mitochondria
Transmission Electron Microscopy
Reperfusion
acetoacetic acid
Assays
Control Groups

Keywords

  • acetoacetate
  • hyperpolarized C-MR
  • mitochondrial dysfunction
  • mitochondrial redox
  • β-hydroxybutyrate

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy

Cite this

@article{9691d8e9bd9a46dfa63b6abb9cd42de8,
title = "Metabolism of hyperpolarized 13 C-acetoacetate to β-hydroxybutyrate detects real-time mitochondrial redox state and dysfunction in heart tissue",
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- 13 C]acetoacetate to [1,3- 13 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) 13 C-acetoacetate (AcAc) to 13 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 13 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 13 C MRS, was validated by a direct measure of tissue β-HB by 1 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 13 C-MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.",
keywords = "acetoacetate, hyperpolarized C-MR, mitochondrial dysfunction, mitochondrial redox, β-hydroxybutyrate",
author = "Wei Chen and Gaurav Sharma and Weina Jiang and Maptue, {Nesmine R.} and Malloy, {Craig R} and Dean Sherry and Chalermchai Khemtong",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/nbm.4091",
language = "English (US)",
journal = "NMR in Biomedicine",
issn = "0952-3480",
publisher = "John Wiley and Sons Ltd",

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TY - JOUR

T1 - Metabolism of hyperpolarized 13 C-acetoacetate to β-hydroxybutyrate detects real-time mitochondrial redox state and dysfunction in heart tissue

AU - Chen, Wei

AU - Sharma, Gaurav

AU - Jiang, Weina

AU - Maptue, Nesmine R.

AU - Malloy, Craig R

AU - Sherry, Dean

AU - Khemtong, Chalermchai

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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- 13 C]acetoacetate to [1,3- 13 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) 13 C-acetoacetate (AcAc) to 13 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 13 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 13 C MRS, was validated by a direct measure of tissue β-HB by 1 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 13 C-MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.

AB - 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- 13 C]acetoacetate to [1,3- 13 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) 13 C-acetoacetate (AcAc) to 13 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 13 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 13 C MRS, was validated by a direct measure of tissue β-HB by 1 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 13 C-MRS may serve as a useful diagnostic marker of mitochondrial redox and dysfunction in heart tissue in vivo.

KW - acetoacetate

KW - hyperpolarized C-MR

KW - mitochondrial dysfunction

KW - mitochondrial redox

KW - β-hydroxybutyrate

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