Regulation of mitochondrial bioenergetics by the non-canonical roles of mitochondrial dynamics proteins in the heart

Abstract

Recent advancement in mitochondrial research has significantly extended our knowledge on the role and regulation of mitochondria in health and disease. One important breakthrough is the delineation of how mitochondrial morphological changes, termed mitochondrial dynamics, are coupled to the bioenergetics and signaling functions of mitochondria. In general, it is believed that fusion leads to an increased mitochondrial respiration efficiency and resistance to stress-induced dysfunction while fission does the contrary. This concept seems not applicable to adult cardiomyocytes. The mitochondria in adult cardiomyocytes exhibit fragmented morphology (tilted towards fission) and show less networking and movement as compared to other cell types. However, being the most energy-demanding cells, cardiomyocytes in the adult heart possess vast number of mitochondria, high level of energy flow, and abundant mitochondrial dynamics proteins. This apparent discrepancy could be explained by recently identified new functions of the mitochondrial dynamics proteins. These "non-canonical" roles of mitochondrial dynamics proteins range from controlling inter-organelle communication to regulating cell viability and survival under metabolic stresses. Here, we summarize the newly identified non-canonical roles of mitochondrial dynamics proteins. We focus on how these fission and fusion independent roles of dynamics proteins regulate mitochondrial bioenergetics. We also discuss potential molecular mechanisms, unique intracellular location, and the cardiovascular disease relevance of these non-canonical roles of the dynamics proteins. We propose that future studies are warranted to differentiate the canonical and non-canonical roles of dynamics proteins and to identify new approaches for the treatment of heart diseases. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.

Keywords: Cardiac bioenergetics; Metabolic heart disease; Mitochondria associated membranes; Mitochondrial dynamics proteins.

Fig. 1

Mitochondrial dynamics proteins orchestrate bioenergetics, redox and Ca²⁺ signaling in cardiac mitochondria.

Fig. 2

Location of the dynamics proteins at or near the MAM in adult cardiomyocyte. A, Left: electron microscopic (EM) image of a portion of an adult cardiomyocyte. Right: enlarged area showing the juxtaposition of mitochondria (red), SR (green) and T Tubule (blue). B, Diagram based on the structural proximity of the organelles shown in A to highlight the enrichment of mitochondrial dynamics proteins at or near MAM. The MAM is within 10–30 nm from the dyad (for EC coupling) and mitochondrial contact site (for mPTP and respiration). The major pathways involving MAM located dynamics proteins are: (1) Drp1 interaction with mPTP components to regulate transient mPTP opening, which stimulates respiration; (2) Mfn1/2 tether mitochondria with SR at MAM to facilitate mitochondrial Ca²⁺ uptake via VDAC and MCU to activate metabolism; and (3) Opa1 maintains the cristae structure at mitochondrial contact site adjacent to MAM, which allows the appropriate assembly and function of ETC complexes. The EM image in A is adopted from a previous report (Ref #68) with permission. Ca²⁺: calcium, Drp1: dynamin related protein 1, ETC: electron transport chain, LCC: L-type Ca²⁺ channel, MAM: mitochondrial associated membrane, MCU: mitochondrial Ca²⁺ uniporter, Mfn1/2: mitofusion 1/2, mPTP: mitochondrial permeability transition pore, Opa1: optic atrophy 1, RyR2: ryanodine receptor 2, VDAC: voltage dependent anion channel.