Altered Mitochondrial Metabolism and Mechanosensation in the Failing Heart: Focus on Intracellular Calcium Signaling

Abstract

The heart consists of millions of cells, namely cardiomyocytes, which are highly organized in terms of structure and function, at both macroscale and microscale levels. Such meticulous organization is imperative for assuring the physiological pump-function of the heart. One of the key players for the electrical and mechanical synchronization and contraction is the calcium ion via the well-known calcium-induced calcium release process. In cardiovascular diseases, the structural organization is lost, resulting in morphological, electrical, and metabolic remodeling owing the imbalance of the calcium handling and promoting heart failure and arrhythmias. Recently, attention has been focused on the role of mitochondria, which seem to jeopardize these events by misbalancing the calcium processes. In this review, we highlight our recent findings, especially the role of mitochondria (dys)function in failing cardiomyocytes with respect to the calcium machinery.

Keywords: calcium transient; fatty acids; mechanoelectric transduction; microdomains; mitochondria metabolism.

Figure 1

Diagram of subcellular interaction between subcellular calcium compartmentation and reactive oxygen species (ROS) in normal (A) and failing (B) cardiomyocytes. LTCC: L-Type Calcium Channel; NCX: Sodium-Calcium Exchanger; HCX: Hydrogen-Calcium Exchanger; mCU: Mitochondria Calcium Uniporter; mPTP: Mitochondrial Permeability Transition Pore; SERCA: Sarco/Endoplasmic Reticulum Ca²⁺-ATPase; IP3R: Inositol Trisphosphate Receptors; RyR: Ryanodine Receptors; ROS: Reactive Oxygen Species; ETC: Electron Transport Chain. Dotted lines indicate Ca²⁺ efflux; full line indicate Ca²⁺ influx.

Figure 2

Schematic representation of nanoscopic technology for interrogates subsarcolemmal mitochondrial mechanosensitivty. Blue dotted line: excitation light. Green dotted line: emission light from the sample.

Figure 3

Membrane compliance related to mechanically induced Ca²⁺ release. (A) Left. SICM topographical image of a failing rat ventricular cardiomyocyte. Asterisks indicate the position where hydrojet pressures were applied (black = partially striated area, red = unstriated area). Right. Pressure vs. Z displacement in the two positions selected on SICM image. To note the unstriated area is stiffer; (B) Membrane compliance (µm/kPa) during progression toward HF (MI-16 weeks (wks)) in crest, groove, and unstriated areas; (C) Mechanically-induced Ca²⁺ release after hydrojet pressure delivery, in AMC cell top and in HF cell bottom. * p < 0.05 vs. control; ** p < 0.001 vs. control. Modified from [6] with permission.

Figure 4

Surface scanning ion conductance microscopy analysis of mitochondrial displacement. (A) SICM images of 10 μm × 10 μm cardiomyocyte regions of AMC (top) and MI (bottom) cells; (B) Surface confocal images (obtained by SSICM) of the labelled TMRM active mitochondria in (A); (C) Merged images for SICM topography TMRM-labelled mitochondria; (D) Mitochondrial displacement observed by TEM. Scale bar: 500 nm Modified from [6] with permission.

Figure 5

Microtubule network derangements together with mitochondrial displacement are prerequisite for mechanically induced Ca²⁺ release initiation. (A) TMRM-labelled mitochondria position in AMC, AMC+colchicine, and HF (MI-16 weeks); (B) Mechanically induced Ca²⁺ initiation in AMC cell (top) and the same cell in the presence of colchicine (bottom); (C) Occurrence of MiCa_i events in terms of no response, focal MiCa_i and total MiCa_i in AMC, AMC+colchicine, AMC+colchcine+CCCP; (D) Same as C for AMC, MI-16 wks, MI-16-wks + Nifedipine, MI-16-wks + CCCP, MI-16-wks + CsA. Modified from [6] with permission.