Mitochondrial proteome remodeling in ischemic heart failure

Abstract

Mitochondrial dysfunction is an important part of the decline in cardiac function in heart failure. Aims We hypothesize that there would be specific abnormalities in mitochondrial function and proteome with the progression of ischemic heart failure (HF). Materials and Methods We used a high left anterior descending artery (LAD)ligation in 3–4 month old male rats to generate HF. Rats were studied 9 weeks post ligation. Key findings Electron microscopy of left ventricle samples showed, mitochondrial changes including decreased size, increased number, abnormal distribution, and cristae loss. Mitochondria in ischemic HF exhibited decreased total ATP, impaired mitochondrial respiration, as well as reduced complex I activity. Analysis of LV mitochondrial proteins by mass spectrometry was performed, and 31 differentially expressed proteins (p < 0.05) of more than 500 total proteins were identified. Of these proteins, 15 were up-regulated and 16 down-regulated in the failing heart. A set of complex I proteins were significantly decreased, consistent with the impairment of complex I activity. There were distinct changes in mitochondrial function and proteome in ischemic HF. Although there were similarities, the distinction between the reported proteomic changed with TAC pressure overload induced HF and ischemic HF in the current study suggested different pathological mechanisms. Significance Specific changes in mitochondrial protein expression, which correlate with changes in mitochondrial function, have been identified in ischemic HF for the first time.

Lack of β, β‐carotene‐9′, 10′‐oxygenase 2 leads to hepatic mitochondrial dysfunction and cellular oxidative stress in mice

“…Based on the proteomics analysis, the expression of ETC/OXPHOS complex I, II, and IV proteins was reduced in the livers of BCO2 KO mice, though the expression of cytochrome c was increased in the BCO2 KO, compared to WT mice. These observations may suggest that a change of mitochondrial proteome occurred in BCO2 KO mice (42–49). Decreased protein expression of the mitochondrial proteome has been linked to hyperactivation of hepatic mitochondria in diabetes and obesity (13, 46).…”

“…The low aconitase activity occurs in obese mice with higher mitochondrial respiration activities (44). Ischemic hearts have a lower mitochondrial complex OCR activity though the mitochondrial complex I protein contents are higher (42). Mitochondria are far more complex in form and function than anticipated and are controlled by multiple factors such as circadian, nutrient availability (e.g., fasting and fed), and protein expressions (47, 49).…”

Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice

“…The activation of chemokine and cytokine receptors may lead to the induction of different downstream pathways, e.g. JAK-STAT and MAP kinase leading to growth or cell differentiation, or AKTassociated apoptosis through regulation mechanisms on mitochondria [23]. Therefore the balance in the expression of chemokines and cytokines is one of the major factors influencing the limitation of the damage, timely onset and rapid pace of remodeling and thereby myocardial survival.…”

Mitochondrial Dynamics and Heart Failure

“…As discussed above, a 10 kDa fragment of OPA1 keeps cristae junctions tightly closed, preventing the release of cytochrome c and apoptosis. Dysfunctional mitochondria have been frequently found to have disruption and loss of cristae, such as reported with ischemic heart failure (32;109), with reduction in OPA1 expression (31;152), in Huntington’s disease (36), and with reduction in Crif1, as occurs with Alzheimer’s disease (9;23). …”