Targeting Mitochondria in Cardiac Disease

Ischemia/reperfusion injury occurs in the heart when there is a blockage in blood flow in a coronary artery, creating an ischemic state, followed by reperfusion. Reperfusion is the return of normal blood flow to an area that was previously cut off. This can lead to oxidative stress within cardiac cells and the promotion of apoptosis. This can reduce the efficiency of the heart and have long term health consequences for the individual after an attack. Previous work has demonstrated that cellular stress, much like that experienced be heart cells during ischemia/reperfusion, can alter the dynamics of mitochondria.

Mitochondria are the organelles responsible for providing ATP, what mammalian cells universally use for energy, and also play a major role apoptosis. Single mitochondrion are not autonomous, they undergo a dynamic process of fusion and fission within cells. The balance between the two is thought to be tightly coordinated in regulating cellular survival and proper development. A new study published in the journal Circulation assessed the dynamics of mitochondria in cardiac cells following cellular insult. In doing so, the authors were able to address whether mitochondria dynamics may represent a therapeutic target in preventing ischemia/reperfusion injury in cells that compose the heart.

The authors used the HL-1 mouse atrial cell line to assess mitochondrial structure after an induced period of ischemia. Interestingly, mitochondria underwent a process of fission in which they fragmented in smaller mitochondrial units. This process could be prevented by expressing a dominant negative form of the fission gene Drp1. That is, they expressed a mutant form of Drp1 that will prevent fission. Likewise, exogenous expression of the fusion proteins, Mfn1 or Mfn2, or treatment with a chemical inhibitor of Drp1, also inhibited fission in response to ischemia. Following ischemia the authors reperfused the cells and assessed cell death. Consistently, under conditions where fission was blocked, less cell death was present. This suggests mitochondrial fission may play a role in cellular damage following ischemia/reperfusion.

To understand the importance of this phenomenon in vivo, the authors induced ischemia/reperfusion in rat hearts in the presence or absence of the Drp1 chemical inhibitor. As with the in vitro experiments, the inhibitor reduced the extent of cellular damage in comparison to controls.

This study is important for understanding the mechanism by which cardiac injury occurs following ischemia/reperfusion. In doing so, it opens the door for future therapeutic avenues to be explored in drug development and clinical trials.

References:

Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ. Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury. Circulation. 2010 Apr 26. [Epub ahead of print]