Investigating the Details of Mitochondrial Dysfunction in the Aging Mouse Heart
This is a look at a specific form of mitochondrial dysfunction in aging heart tissue, with a focus on the sarcoplasmic reticulum structure inside cells responsible for, among other things, storing and pumping calcium ions. Calcium has many roles; calcium ions (Ca2+) are important in signaling for muscle contractions for example. Here it seems that the problem lies in the interaction between two cellular organelles, and is more subtle than just damage to one or other:
Mitochondrial alterations are critically involved in increased vulnerability to disease during aging. We investigated the contribution of mitochondria-sarcoplasmic reticulum (SR) communication in cardiomyocyte functional alterations during aging. Heart function [was] preserved in hearts from old mice (20 months) with respect to young mice (5 - 6 months). Mitochondrial membrane potential and resting O2 consumption were similar in mitochondria from young and old hearts. However, maximal ADP-stimulated O2 consumption was specifically reduced in interfibrillar mitochondria from aged hearts.Second generation proteomics disclosed an increased mitochondrial protein oxidation in advanced age. Because energy production and oxidative status are regulated by mitochondrial Ca2+, we investigated the effect of age on mitochondrial Ca2+ uptake. Although no age-dependent differences were found in Ca2+ uptake kinetics in isolated mitochondria, mitochondrial Ca2+ uptake secondary to SR Ca2+ release was significantly reduced in cardiomyocytes from old hearts, and this effect was associated with decreased NAD(P)H regeneration and increased mitochondrial reactive oxygen species (ROS) upon increased contractile activity.
[We] identified the defective communication between mitochondrial voltage-dependent anion channel and SR ryanodine receptor (RyR) in cardiomyocytes from aged hearts associated with altered Ca2+ handling. Age-dependent alterations in SR Ca2+ transfer to mitochondria and in Ca2+ handling could be reproduced in cardiomyoctes from young hearts after interorganelle disruption with colchicine, at concentrations that had no effect in aged cardiomyocytes or isolated mitochondria. Thus, defective SR-mitochondria communication underlies inefficient interorganelle Ca2+ exchange that contributes to energy demand/supply mismatch and oxidative stress in the aged heart.