Enforcing linear architectural organization in human cardiomyocytes using micropatterned substrates enhanced mitochondrial bioenergetic efficiency and sarcoplasmic reticulum-mitochondria interactions compared to unconstrained conditions.
Does structural alignment using micropatterned substrates improve mitochondrial respiration and bioenergetic efficiency in human induced pluripotent stem cell-derived cardiomyocytes compared to unconstrained culture conditions?
Enforcing linear architectural organization in human cardiomyocytes enhances mitochondrial bioenergetic efficiency by increasing sarcoplasmic reticulum-mitochondria interactions, providing mechanistic insights into heart failure driven by myocardial disarray.
Adult cardiomyocytes are embedded within a highly organized myocardial microenvironment that imposes critical geometric cues essential for the alignment and distribution of organelles and the shaping of their unique, rectangular cellular morphology. Despite the association of cardiomyocyte disarray with human heart disease, the functional consequences of this cellular disorganization remain poorly understood. Here, we leveraged micropatterned substrates to promote structural alignment in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), contrasting the effects of mechanical alignment on mitochondrial form and function with hiPSC-CMs cultured under standard unconstrained conditions. Cardiomyocytes cultured under unconstrained conditions exhibited misaligned sarcomeres and a perinuclear mitochondrial distribution while micropatterned hiPSC-CMs developed linear myofibrils and reconfigured sarcomere and mitochondrial organization, which increased mitochondrial respiration without augmenting mitochondrial mass. Notably, micropatterned hiPSC-CMs exhibited an increased number of mitochondria-associated membranes, as determined by proximity ligation assays and transmission electron microscopy, suggesting enhanced interactions between the sarcoplasmic reticulum and mitochondria. Together, these findings demonstrate that mitochondrial-sarcoplasmic architecture and geometry are critical spatial features that ensure bioenergetic efficiency of cardiomyocytes. This work underscores the importance of cellular organization in cardiomyocyte metabolism and function, providing insights into the pathophysiology of cardiac diseases marked by cellular disarray.
Jouve et al. (Thu,) conducted a other in Myocardial disarray (in vitro model). Linear micropatterned substrates vs. Standard unconstrained conditions (non-patterned) was evaluated on Mitochondrial respiration (oxygen consumption rate) and structural organization. Enforcing linear architectural organization in human cardiomyocytes using micropatterned substrates enhanced mitochondrial bioenergetic efficiency and sarcoplasmic reticulum-mitochondria interactions compared to unconstrained conditions.