Calcium Signaling and Reactive Oxygen Species in Mitochondria

Circ Res. 2018 May 11;122(10):1460-1478. doi: 10.1161/CIRCRESAHA.118.310082.


In heart failure, alterations of Na+ and Ca2+ handling, energetic deficit, and oxidative stress in cardiac myocytes are important pathophysiological hallmarks. Mitochondria are central to these processes because they are the main source for ATP, but also reactive oxygen species (ROS), and their function is critically controlled by Ca2+ During physiological variations of workload, mitochondrial Ca2+ uptake is required to match energy supply to demand but also to keep the antioxidative capacity in a reduced state to prevent excessive emission of ROS. Mitochondria take up Ca2+ via the mitochondrial Ca2+ uniporter, which exists in a multiprotein complex whose molecular components were identified only recently. In heart failure, deterioration of cytosolic Ca2+ and Na+ handling hampers mitochondrial Ca2+ uptake and the ensuing Krebs cycle-induced regeneration of the reduced forms of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate), giving rise to energetic deficit and oxidative stress. ROS emission from mitochondria can trigger further ROS release from neighboring mitochondria termed ROS-induced ROS release, and cross talk between different ROS sources provides a spatially confined cellular network of redox signaling. Although low levels of ROS may serve physiological roles, higher levels interfere with excitation-contraction coupling, induce maladaptive cardiac remodeling through redox-sensitive kinases, and cell death through mitochondrial permeability transition. Targeting the dysregulated interplay between excitation-contraction coupling and mitochondrial energetics may ameliorate the progression of heart failure.

Keywords: heart failure; metabolism; mitochondria; oxidant stress; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Transport
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling*
  • Dogs
  • Excitation Contraction Coupling
  • Heart Failure / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart / metabolism*
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / physiology
  • Myocytes, Cardiac / metabolism
  • NADP Transhydrogenase, AB-Specific / deficiency
  • NADP Transhydrogenase, AB-Specific / physiology
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism*
  • Sodium / metabolism


  • Calcium Channels
  • Mitochondrial Proteins
  • Oligopeptides
  • Reactive Oxygen Species
  • arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
  • mitochondrial calcium uniporter
  • Sodium
  • NADP Transhydrogenase, AB-Specific
  • NNT protein, human
  • Nnt protein, mouse
  • Calcium