Mitochondrial Arrest on the Microtubule Highway—A Feature of Heart Failure and Diabetic Cardiomyopathy?

Figures

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  Figure 1. Putative molecular mechanisms of mitochondrial movement. (A) In the absence of cytosolic Ca2+ (nM) Miro1 (bound to the outer mitochondrial membrane) coordinates mitochondrial movement along microtubules via KIF5A, TRAK1 and Mfn2. According to literature Ca2+ binding leads to two possible scenarios; (B) Conformational changes to Miro1, and subsequent detachment from Mfn2 and release of KIF5A from the microtubule trafficking apparatus, or (C) Detachment of Miro1 from Mfn2 and a disruption between TRAK1 and KIF5A interactions. Both scenarios result in halted mitochondrial movement.

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  Figure 2. Schematic overview of proposed mechanism of action of HDAC6 and associated deacetylation; linking mitochondrial motility, inflammation and the putative involvement of post-translational modifications in DCM. Inflammation/diabetic insult triggers HDAC6 activity which directly interacts with NLRP3 via ubiquitin binding domains (although it is unknown whether this activates/inactivates NLRP3 and inflammasome assembly in the heart). The combination of microtubule (alpha-tubulin) destabilisation and reduced acetylation (important for microtubule stability), contributes to disengagement of the mitochondria from the microtubule apparatus and halts mitochondrial movement. With mitochondrial motility linked to mitophagy, the removal of damaged mitochondria (potentially ROS producing) is impaired, leading to subsequent mitochondrial dysfunction, and oxidative stress further exacerbating inflammation via NLRP3. Inhibition of HDAC6 activity is also reported as cardioprotective.