Biochemical and biophysical research communications · 2026
Inhibition of mitochondrial complex I by rotenone reduces arterial calcification in vitro.
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Gorgels Andrea, Köneke Tabea, Karimian Setareh, Moellmann Julia, Noels Heidi, Marx Nikolaus, Goettsch Claudia
Аннотация
AIM: Cardiovascular diseases are the leading cause of death worldwide, with arterial calcification being a risk factor, especially in patients with diabetes and kidney disease. Arterial calcification involves hydroxyapatite deposition and the transformation of vascular smooth muscle cells (vSMCs) into osteoblast-like cells, processes mediated in part by tissue-nonspecific alkaline phosphatase (TNAP, encoded by ALPL), a key regulator of mineralization. Previous work showed increased activity of electron transport chain complexes I and IV during vSMC calcification. This study examined the role of mitochondrial complex I in vSMC calcification.
METHODS: vSMCs were calcified using osteogenic medium. Rotenone was used as a complex I inhibitor. Metabolomic profiling, extracellular pH measurements, and TNAP activity assays were performed.
RESULTS: Rotenone dose-dependently reduced matrix mineralization, with near-complete inhibition at 50 nM, without affecting cell viability. Metabolomic analysis showed that rotenone increased both intracellular and extracellular lactic acid while decreasing pyruvic acid, indicating a shift toward glycolysis. Exogenous lactic acid reduced mineralization by 24%; sodium lactate reduced mineralization without altering extracellular pH; and extracellular acidification independently reduced mineralization by 23%, indicating that both lactate and proton-mediated acidification partially contribute to the anti-calcific mechanism. Additionally, rotenone decreased TNAP activity by 59% without affecting ALPL transcript levels.
CONCLUSION: Inhibition of mitochondrial complex I causes metabolic reprogramming in calcifying vSMCs, promoting lactic acid accumulation that partially inhibits matrix mineralization through lactate-mediated and acidification-dependent mechanisms. The near-complete inhibition of calcification by rotenone suggests additional uncharacterized mechanisms beyond the lactic acid-pH axis contribute to its full anti-calcific effect, warranting further investigation.
METHODS: vSMCs were calcified using osteogenic medium. Rotenone was used as a complex I inhibitor. Metabolomic profiling, extracellular pH measurements, and TNAP activity assays were performed.
RESULTS: Rotenone dose-dependently reduced matrix mineralization, with near-complete inhibition at 50 nM, without affecting cell viability. Metabolomic analysis showed that rotenone increased both intracellular and extracellular lactic acid while decreasing pyruvic acid, indicating a shift toward glycolysis. Exogenous lactic acid reduced mineralization by 24%; sodium lactate reduced mineralization without altering extracellular pH; and extracellular acidification independently reduced mineralization by 23%, indicating that both lactate and proton-mediated acidification partially contribute to the anti-calcific mechanism. Additionally, rotenone decreased TNAP activity by 59% without affecting ALPL transcript levels.
CONCLUSION: Inhibition of mitochondrial complex I causes metabolic reprogramming in calcifying vSMCs, promoting lactic acid accumulation that partially inhibits matrix mineralization through lactate-mediated and acidification-dependent mechanisms. The near-complete inhibition of calcification by rotenone suggests additional uncharacterized mechanisms beyond the lactic acid-pH axis contribute to its full anti-calcific effect, warranting further investigation.