Old players in a new role: mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria

Cell Calcium. Nov-Dec 2002;32(5-6):363-77. doi: 10.1016/s0143416002001872.


In many cell types, IP(3) and ryanodine receptor (IP(3)R/RyR)-mediated Ca(2+) mobilization from the sarcoendoplasmic reticulum (ER/SR) results in an elevation of mitochondrial matrix [Ca(2+)]. Although delivery of the released Ca(2+) to the mitochondria has been established as a fundamental signaling process, the molecular mechanism underlying mitochondrial Ca(2+) uptake remains a challenge for future studies. The Ca(2+) uptake can be divided into the following three steps: (1) Ca(2+) movement from the IP(3)R/RyR to the outer mitochondrial membrane (OMM); (2) Ca(2+) transport through the OMM; and (3) Ca(2+) transport through the inner mitochondrial membrane (IMM). Evidence has been presented that Ca(2+) delivery to the OMM is facilitated by a local coupling between closely apposed regions of the ER/SR and mitochondria. Recent studies of the dynamic changes in mitochondrial morphology and visualization of the subcellular pattern of the calcium signal provide important clues to the organization of the ER/SR-mitochondrial interface. Interestingly, key steps of phospholipid synthesis and transfer to the mitochondria have also been confined to subdomains of the ER tightly associated with the mitochondria, referred as mitochondria-associated membranes (MAMs). Through the OMM, the voltage-dependent anion channels (VDAC, porin) have been thought to permit free passage of ions and other small molecules. However, recent studies suggest that the VDAC may represent a regulated step in Ca(2+) transport from IP(3)R/RyR to the IMM. A novel proposal regarding the IMM Ca(2+) uptake site is a mitochondrial RyR that would mediate rapid Ca(2+) uptake by mitochondria in excitable cells. An overview of the progress in these directions is described in the present paper.

Publication types

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

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / physiology*
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism
  • Intracellular Membranes / physiology*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / physiology*
  • Porins / metabolism*
  • Porins / physiology
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Ryanodine Receptor Calcium Release Channel / physiology
  • Voltage-Dependent Anion Channels


  • Porins
  • Ryanodine Receptor Calcium Release Channel
  • Voltage-Dependent Anion Channels