The Role of Mitochondria in the Mechanisms of Cardiac Ischemia-Reperfusion Injury

Abstract

Mitochondria play a critical role in maintaining cellular function by ATP production. They are also a source of reactive oxygen species (ROS) and proapoptotic factors. The role of mitochondria has been established in many aspects of cell physiology/pathophysiology, including cell signaling. Mitochondria may deteriorate under various pathological conditions, including ischemia-reperfusion (IR) injury. Mitochondrial injury can be one of the main causes for cardiac and other tissue injuries by energy stress and overproduction of toxic reactive oxygen species, leading to oxidative stress, elevated calcium and apoptotic and necrotic cell death. However, the interplay among these processes in normal and pathological conditions is still poorly understood. Mitochondria play a critical role in cardiac IR injury, where they are directly involved in several pathophysiological mechanisms. We also discuss the role of mitochondria in the context of mitochondrial dynamics, specializations and heterogeneity. Also, we wanted to stress the existence of morphologically and functionally different mitochondrial subpopulations in the heart that may have different sensitivities to diseases and IR injury. Therefore, various cardioprotective interventions that modulate mitochondrial stability, dynamics and turnover, including various pharmacologic agents, specific mitochondrial antioxidants and uncouplers, and ischemic preconditioning can be considered as the main strategies to protect mitochondrial and cardiovascular function and thus enhance longevity.

Keywords: cytoskeleton; energy metabolism; heart; ischemia-reperfusion; mitochondria; mitochondrial heterogeneity; preconditioning; reactive oxygen species; signaling.

Figure 1

(A) The roles of mitochondria in normal cell function; and (B) in various cell damage/injuries. Mitochondrial function and dysfunction contribute to cell viability and injury by several mechanisms. ROS—reactive oxygen species.

Figure 2

Fluorescence confocal evidence for the co-localization of the (A) tubulin beta II (Tub β II) (visualized by the specific antibodies against tubulin beta II, green), with mitochondria (Mito) (B) visualized by the specific mitochondrial potential-sensitive probe tetramethylrhodamine methyl ester (TMRM, red). Merged image (C).

Figure 3

A scheme summarizing hypotheses regarding the possible origin and mechanisms contributing to the heterogeneity of mitochondria and mitochondrial function. Complex communications of mitochondria with a cell at rest and factors which can be involved in the formation of mitochondrial heterogeneity are shown. ΔΨ—mitochondrial potential. AMPK—AMP-activated protein kinase; PKC—protein kinase C; UCPs—uncoupling proteins; AIF—apoptosis- inducing factor; Raf—rapidly accelerated fibrosarcoma (RAF protein kinases); AKT—Protein kinase B (Akt, serine/threonine protein kinase); Bcl-2—(B-cell lymphoma 2 protein) antagonist of cell death.

Figure 4

Mitochondrial heterogeneity and subpopulations. Mitochondrial subsets may have different region-specific specializations depending on their intracellular localization and environment (A). Mitochondrial subpopulations in a cardiac cell: SS—subsarcolemmal, IM—intermyofibrillar and PN—perinuclear mitochondria visualized by TMRM (red) (B). SS (subsarcolemmal) mitochondrial clusters in soleus muscles (M. soleus) visualized from the auto-fluorescence of mitochondrial flavoproteins, fluorescent in their oxidized state (green) (C).

Figure 5

Laser irradiation as a tool for mitochondrial production of ROS. Note a significant heterogeneity of mitochondria in the cell in relation to mitoROS levels and degrees of mitochondrial depolarization (decline in the inner-membrane potential). mitoROS were visualized with 2,7-dihydrodichlorofluorescein (DCF) by 488 nm laser irradiation. Mitochondrial membrane potential was monitored with tetramethylrhodamine methyl ester (TMRM) by simultaneous 543 nm laser irradiation.