Mitochondrial Morphology, Dynamics, and Function in Human Pressure Overload or Ischemic Heart Disease With Preserved or Reduced Ejection Fraction

Abstract

Background: The FOXO3a (forkhead box O3a)-BNIP3 (B-cell lymphoma 2/adenovirus E1B 19kDa interacting protein 3) pathway modulates mitochondrial dynamics and function and contributes to myocardial remodeling in rodent models of heart failure. We sought to investigate the expression of this pathway along with the expression of mitochondrial biogenesis (PGC-1α [peroxisome proliferator-activated receptor-γ coactivator-1α]), dynamics (DRP-1 [dynamin-related protein 1], OPA-1 [optic atrophy 1], and MFN 2 [mitofusin 2]), and oxidative phosphorylation (citrate synthase and electron transport chain complexes) markers and COX IV (cytochrome C oxidase) activity in myocardium from patients with valvular or ischemic heart disease and heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF). Methods and Results: Subepicardial left ventricular biopsies (10×1×1 mm 3 ) were obtained at aortic valve replacement (HFpEF AVR , n=5; and HFrEF AVR , n=4), coronary artery bypass grafting (HFpEF CABG , n=5; and HFrEF CABG , n=5), or left ventricular assist device implantation (HFrEF LVAD , n=4). Subepicardial biopsies from patients with normal left ventricular function (n=2) and from donor hearts (n=3) served as controls (normal). Relative to normal, mitochondrial fragmentation and cristae destruction were evident, and mitochondrial area was decreased in HFpEF; 1.00±0.09 versus 0.71±0.08; P =0.016. These mitochondrial morphological changes were more pronounced in HFrEF (0.54±0.06); P =0.002 HFpEF versus HFrEF. BNIP3 (monomer+dimer) expression was increased in HFpEF (3.99±2.44) and in HFrEF (5.19±1.70) relative to normal; P =0.004 and P <0.001, respectively. However, BNIP3 monomer was increased in HFrEF (4.32±1.43) compared with normal (0.99±0.06) and HFpEF (1.97±0.90); P =0.001 and 0.004, respectively. The HFrEF group uniquely showed increase in DRP-1 expression (1.94±0.38) and decreases in PGC-1α expression (0.61±0.07) and COX IV activity (0.70±0.10) relative to normal; P =0.013, P <0.001, and P <0.001, respectively, with no significant change in electron transport chain complexes expression. Conclusions: These findings in human myocardium confirm studies in rodents where contractile dysfunction is associated with activation of the FOXO3a-BNIP3 pathway and altered mitochondrial dynamics, biogenesis, and function.

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…The deleterious effects of stress-induced OPA1 processing on myocardial function reveal the link between cardiac metabolism and mitochondrial dynamics [39]. The mitochondrial area and ultrastructure are deranged in heart failure with reduced ejection fraction (HFrEF), where the markers of mitochondrial fission dynamin-related protein-1 (DRP1) are deranged 3 Oxidative Medicine and Cellular Longevity [40]. The balance between fusion and fission is crucial to maintaining heart health [41].…”

Investigating the roles of cyclin C in the mammalian heart

“…Results illustrate that the cyclin C gene, CCNC, expression is frequently altered in different types of cancer 87 . The human CCNC gene is located within a region of chromosome 6q21 that is commonly deleted in breast, lung and ovarian cancers, in addition to prostate carcinomas, human acute lymphoblastic leukemia and osteosarcomas 87,[90][91] . In contrast, amplification of CCNC is related to poor prognosis in patients with colon adenocarcinomas 92 .…”

“…This rule applies to cyclin C, as it is stabilized by catalytically active and inactive Cdk8, whereas free cyclin C is unstable and undergoes rapid ubiquitination and subsequent degradation 86 . In addition to binding and activating Cdk8, cyclin C has also been shown to interact with multiple kinases in different cell types, highlighting its functional versatility and redundancy (Table 4) 76,87,88 .…”

“…In addition, double knock down of CCNC and Cdk19 occurs in 7% of diffuse large B-cell lymphomas (DLBCL) 87 . Together, these study shows that cyclin C functions as a tumor suppressor by preventing stabilization, hence accumulation of ICN1.…”

“…The constant electrical and mechanical activities of the heart require a continuous energy supply met by a rich stockpile of mitochondria 87 , which maintain proper function by undergoing a constant cycle of fusion (i.e., process of merging the double membrane of two mitochondria 13 ) and fission (i.e., process of mitochondrial division) 7,24,88,89 . Mitochondria fission is a normal mechanism to maintain a population of healthy mitochondria; however, a dramatic increase in fission (hyper-fission or fragmentation) can be detrimental to the cell [90][91][92][93] .…”