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Complex Effects of Putative DRP-1 Inhibitors on Stress Responses in Mouse Heart and Rat Cardiomyoblasts
Lauren Wendt1, Jelena Vider1, Louise E See Hoe1
1School of Medical Science, Griffith University, Southport, Australia (L.W., J.V., E.D.T., J.N.P., J.P.H.) and Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Chermside, Australia (L.E.S.H.).
Abstract:
Dynamin-related protein-1 (DRP-1)-dependent mitochondrial fission may influence cardiac tolerance to ischemic or oxidative stress, presenting a potential "cardioprotective" target. Effects of dynamin inhibitors [mitochondrial division inhibitor 1 (MDIVI-1) and dynasore] on injury, mitochondrial function, and signaling proteins were assessed in distinct models: ischemia-reperfusion (I-R) in mouse hearts and oxidative stress in rat H9c2 cardiomyoblasts. Hearts exhibited substantial cell death [approx. 40 IU lactate dehydrogenase (LDH) efflux] and dysfunction (approx. 40 mmHg diastolic pressure, approx. 40% contractile recovery) following 25 minutes' ischemia. Pretreatment with 1 μM MDIVI-1 reduced dysfunction (30 mmHg diastolic pressure, approx. 55% recovery) and delayed without reducing overall cell death, whereas 5 μM MDIVI-1 reduced overall death at the same time paradoxically exaggerating dysfunction. Postischemic expression of mitochondrial DRP-1 and phospho-activation of ERK1/2 were reduced by MDIVI-1. Conversely, 1 μM dynasore worsened cell death and reduced nonmitochondrial DRP-1. Postischemic respiratory fluxes were unaltered by MDIVI-1, although a 50% fall in complex-I flux control ratio was reversed. In H9c2 myoblasts stressed with 400 μM H2O2, treatment with 50 μM MDIVI-1 preserved metabolic (MTT assay) and mitochondrial (basal respiration) function without influencing survival. This was associated with differential signaling responses, including reduced early versus increased late phospho-activation of ERK1/2, increased phospho-activation of protein kinase B (AKT), and differential changes in determinants of autophagy [reduced microtubule-associated protein 1 light chain 3b (LC3B-II/I) vs. increased Parkinson juvenile disease protein 2 (Parkin)] and apoptosis [reduced poly-(ADP-ribose) polymerase (PARP) cleavage vs. increased BCL2-associated X (BAX)/B-cell lymphoma 2 (BCL2)]. These data show MDIVI-1 (not dynasore) confers some benefit during I-R/oxidative stress. However, despite mitochondrial and metabolic preservation, MDIVI-1 exerts mixed effects on cell death versus dysfunction, potentially reflecting differential changes in survival kinase, autophagy, and apoptosis pathways. SIGNIFICANCE STATEMENT: Inhibition of mitochondrial fission is a novel approach to still elusive cardioprotection. Assessing effects of fission inhibitors on responses to ischemic or oxidative stress in hearts and cardiomyoblasts reveals mitochondrial division inhibitor 1 (MDIVI-1) and dynasore induce complex effects and limited cardioprotection. This includes differential impacts on death and dysfunction, survival kinases, and determinants of autophagy and apoptosis. Although highlighting the interconnectedness of fission and these key processes, results suggest MDIVI-1 and dynasore may be of limited value in the quest for effective cardioprotection.
Insights
Mitochondrial fission inhibition shows limited cardioprotection. Mitochondrial division inhibitor 1 (MDIVI-1) offers some benefit against ischemia-reperfusion and oxidative stress, but with mixed effects on cell death and dysfunction.
Area of Science:
- Cardiovascular Research
- Mitochondrial Biology
- Cellular Stress Response
Background:
- Dynamin-related protein-1 (DRP-1)-dependent mitochondrial fission is a potential target for cardioprotection.
- Understanding the effects of dynamin inhibitors on cardiac tolerance to stress is crucial.
Purpose of the Study:
- To assess the effects of dynamin inhibitors, MDIVI-1 and dynasore, on cardiac injury, mitochondrial function, and signaling pathways.
- To investigate the potential cardioprotective roles of inhibiting mitochondrial fission in models of ischemia-reperfusion and oxidative stress.
Main Methods:
- Experiments were conducted using ischemia-reperfusion in mouse hearts and oxidative stress in rat H9c2 cardiomyoblasts.
- Dynamin inhibitors (MDIVI-1 and dynasore) were administered to assess their impact on cell death, cardiac function, mitochondrial respiration, and key signaling proteins.
Main Results:
- MDIVI-1 demonstrated mixed effects: reduced cardiac dysfunction but delayed cell death at low doses, while higher doses reduced cell death but exaggerated dysfunction.
- MDIVI-1 altered postischemic expression of mitochondrial DRP-1 and ERK1/2 activation, and partially reversed complex-I flux control ratio changes.
- In cardiomyoblasts, MDIVI-1 preserved metabolic and mitochondrial function without affecting survival, associated with differential modulation of ERK1/2, AKT, autophagy, and apoptosis pathways.
Conclusions:
- MDIVI-1, but not dynasore, provided some benefit in models of cardiac stress, though its effects on cell death versus dysfunction were complex.
- The study highlights the interconnectedness of mitochondrial fission with survival kinases, autophagy, and apoptosis.
- Current dynamin inhibitors like MDIVI-1 and dynasore may have limited value for effective cardioprotection due to their multifaceted and sometimes paradoxical effects.
