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

Abstract

A pathophysiological consequence of both type 1 and 2 diabetes is remodelling of the myocardium leading to the loss of left ventricular pump function and ultimately heart failure (HF). Abnormal cardiac bioenergetics associated with mitochondrial dysfunction occurs in the early stages of HF. Key factors influencing mitochondrial function are the shape, size and organisation of mitochondria within cardiomyocytes, with reports identifying small, fragmented mitochondria in the myocardium of diabetic patients. Cardiac mitochondria are now known to be dynamic organelles (with various functions beyond energy production); however, the mechanisms that underpin their dynamism are complex and links to motility are yet to be fully understood, particularly within the context of HF. This review will consider how the outer mitochondrial membrane protein Miro1 (Rhot1) mediates mitochondrial movement along microtubules via crosstalk with kinesin motors and explore the evidence for molecular level changes in the setting of diabetic cardiomyopathy. As HF and diabetes are recognised inflammatory conditions, with reports of enhanced activation of the NLRP3 inflammasome, we will also consider evidence linking microtubule organisation, inflammation and the association to mitochondrial motility. Diabetes is a global pandemic but with limited treatment options for diabetic cardiomyopathy, therefore we also discuss potential therapeutic approaches to target the mitochondrial-microtubule-inflammatory axis.

The Role of Mitochondria in Metabolic Syndrome–Associated Cardiomyopathy

“…Thus, the heart muscle is vulnerable to mitochondria damage. Sarah et al first reported the increased mitochondrial fission in the myocardium of diabetic patients [ 45 ]. Lately, other studies found that FA metabolism in the hearts of asymptomatic diabetic patients significantly increased to compensate for the decreased respiratory capacity, suggesting that changes in mitochondrial metabolism are detrimental to the heart [ 46 , 47 ].…”

A Nanobody-Based Toolset to Monitor and Modify the Mitochondrial GTPase Miro1

“…The emerging role of Miro1 in the development and progression of diseases, particularly neurological disorders, underscores the need for new methods and tools to study this protein in detail at the molecular level (Fatiga et al, 2021;Kassab et al, 2021;Kontou et al, 2021;López-Doménech et al, 2021;Nguyen et al, 2021).…”

“…The emerging role of Miro1 in the development and progression of diseases, particularly neurological disorders, underscores the need for new methods and tools to study this protein in detail at the molecular level ( Fatiga et al, 2021 ; Kassab et al, 2021 ; Kontou et al, 2021 ; López‐Doménech et al, 2021 ; Nguyen et al, 2021 ). Currently, most studies rely on ectopic expression of genetically modified (tagged) Miro1 ( Kanfer et al, 2015 ; Castro et al, 2018 ; Nemani et al, 2018 ; Fatiga et al, 2021 ) which previously has been shown to affect mitochondrial morphology and transport in living cells ( Fransson et al, 2006 ).…”

Mitochondrial Transfer in Cardiovascular Disease: From Mechanisms to Therapeutic Implications

“…Miro1 is a tail-anchored mitochondrial outer membrane protein. After combing with the adaptor protein TRAK1/2, Miro1 can recruit motor proteins (such as kinesin) and initiate microtubule-based mitochondrial movement (37). In a cardiomyocytes and cardiac myofibroblasts co-culture system, mitochondrial transport along microtubules in TNTs is mediated by KIF5B, which is a membrane of the kinesin superfamily (23).…”