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

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Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy

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