Fig. 7. Aβ₄₂ inhibits mitochondrial complex I in cardiomyocytes.

a Basal oxygen consumption rate (OCR) in primary mouse neonatal cardiomyocytes (NVCM) exposed to ScrAβ₄₂ or Aβ₄₂ (ScrAβ₄₂ at 300 (++), 100 (+) and 0pM (−) and co-incubated with Aβ₄₂ at 0 (−), 200 (+) and 300pM (++) for 48 hrs (one-way ANOVA (P < 0.0001; F(2,15) = 53.5) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). b maximal OCR in primary NVCM exposed to ScrAβ₄₂ or Aβ₄₂ for 48 hrs (one-way ANOVA (P = 0.0001; F(2,15) = 31.2) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). c inhibition of respiration in response to increasing concentrations of rotenone in primary NVCM exposed to ScrAβ₄₂ or Aβ₄₂ for 48 hrs (multiple t-tests P.adjusted; n = 5 biological replicates/group). d absolute complex I (CI) OCR in primary NVCM exposed to ScrAβ₄₂ or Aβ₄₂ for 48 hrs (one-way ANOVA (P < 0.0001; F(2,15) = 88.4) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). e complex I (CI) OCR as a percentage of total respiratory capacity in primary NVCM exposed to ScrAβ₄₂ or Aβ₄₂ for 48 hrs (one-way ANOVA (P < 0.0012; F(2,15) = 10.8) with Sidak’s repeated measures test P.adjusted; n = 6 biological replicates/group). All data are mean ± SEM. All statistical tests are two-tailed. Source data are provided in the Source Data file. f schematic of proposed model whereby adipose tissue release of Aβ₄₂ is increased in obesity resulting in higher circulating levels of Aβ₄₂. Increased circulating Aβ₄₂ inhibits cardiomyocyte mitochondrial ATP production and causes diastolic dysfunction, which starts the progression towards heart failure. The effects of Aβ₄₂ on cardiomyocytes could be mediated through receptor-mediated signalling, receptor-mediated internalisation, or direct internalisation. e was created with BioRender.com.