Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Energy Metabolism* ; Oxidative Phosphorylation*; Calcium/*metabolism ; Kidney/*metabolism ; Mitochondria, Heart/*metabolism; Animals ; Cell Respiration ; Models, Biological ; Oxygen Consumption/physiology ; Rats, Sprague-Dawley ; Substrate Specificity ; Time Factors ; Rats

Mitochondrial dehydrogenases are differentially stimulated by Ca ²⁺ . Ca ²⁺ has also diverse regulatory effects on mitochondrial transporters and other enzymes. However, the consequences of these regulatory effects on mitochondrial oxidative phosphorylation (OxPhos) and ATP production, and the dependencies of these consequences on respiratory substrates, have not been investigated between the kidney and heart despite the fact that kidney energy requirements are second only to those of the heart. Our objective was, therefore, to elucidate these relationships in isolated mitochondria from the kidney outer medulla (OM) and heart. ADP-induced mitochondrial respiration was measured at different CaCl 2 concentrations in the presence of various respiratory substrates, including pyruvate + malate (PM), glutamate + malate (GM), alpha-ketoglutarate + malate (AM), palmitoyl-carnitine + malate (PCM), and succinate + rotenone (SUC + ROT). The results showed that, in both heart and OM mitochondria, and for most complex I substrates, Ca ²⁺ effects are biphasic: small increases in Ca ²⁺ concentration stimulated, while large increases inhibited mitochondrial respiration. Furthermore, significant differences in substrate- and Ca ²⁺ -dependent O 2 utilization towards ATP production between heart and OM mitochondria were observed. With PM and PCM substrates, Ca ²⁺ showed more prominent stimulatory effects in OM than in heart mitochondria, while with GM and AM substrates, Ca ²⁺ had similar biphasic regulatory effects in both OM and heart mitochondria. In contrast, with complex II substrate SUC + ROT, only inhibitory effects on mitochondrial respiration was observed in both the heart and the OM. We conclude that the regulatory effects of Ca ²⁺ on mitochondrial OxPhos and ATP synthesis are biphasic, substrate-dependent, and tissue-specific.

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R01 HL151587 United States HL NHLBI NIH HHS; P01 HL116264 United States HL NHLBI NIH HHS

Keywords: ATP synthesis; calcium regulation; energy metabolism; mitochondrial respiration; oxidative phosphorylation; respiratory control; substrate utilization

SY7Q814VUP (Calcium)

Date Created: 20220111 Date Completed: 20220303 Latest Revision: 20240226

20240226

PMC8750792

10.3390/cells11010131

35011693