Am J Physiol Heart Circ Physiol. 2025 Jun 30.
Claire Fong-McMaster,
Ella McIlroy,
Michelle M Levesque,
Stephanie Myers,
Serena M Pulente,
Gurrose Gahla,
Ilka Lorenzen-Schmidt,
Miroslava Cuperlovic-Culf,
Arsalan S Haqqani,
Erin E Mulvihill,
Mary-Ellen Harper.
Heart failure is characterized by metabolic derangements such as altered substrate metabolism and mitochondrial dysfunction. Mitochondrial supercomplexes, which are higher-order molecular structures comprised of multi-subunit complexes of the electron transport chain, are decreased in heart failure. To investigate the supercomplex proteome composition in heart failure, we used an in vivo myocardial infarction (MI) model in which mice exhibited reduced cardiac function, confirmed by two-dimensional echocardiography at 4 weeks post-infarction. To assess proteins within supercomplexes, we used an emerging technique known as complexome profiling. This technique involved separating out mitochondrial protein complexes using Blue-Native PAGE combined with mass spectrometry to identify proteins within supercomplex gel bands. We identified band-dependent decreases or increases in the relative abundance of subunits of the electron transport chain between MI and sham mice. Decreased abundance of proteins involved in α-ketoglutarate dehydrogenase metabolism including DLST was also identified in the supercomplex bands of MI mice compared to sham mice. In addition, decreased abundance of redox-related proteins such as SOD2 and changes in ribosome protein subunits were identified in the MI mitochondria. In conclusion, we identified changes in the mitochondrial supercomplex proteome in a murine model of heart failure, providing insight and novel mechanisms that may be contributing to the metabolic dysfunction in heart failure.
Keywords: Blue-Native PAGE; Respirasome; cardiomyopathy; mass spectrometry; oxidative phosphorylation