Mitochondria Are Excitable Organelles Capable of Generating and Conveying Electrical and Calcium Signals

Abstract

We report Ca2(+)-induced release of Ca2+ from mitochondria (mCICR) dependent on transitory opening of the permeability transition pore (PTP) operating in a low conductance mode. The Ca2+ fluxes taking place during mCICR are a direct consequence of the mitochondrial depolarization spike (mDPS) caused by PTP opening. Both mDPS and mCICR can propagate from one mitochondrion to another in vitro, generating traveling depolarization and Ca2+ waves. Mitochondria thus appear to be excitable organelles capable of generating and conveying electrical and Ca2+ signals. In living cells, mDPS/mCICR is triggered during IP3-induced Ca2+ mobilization and results in the amplification of the Ca2+ signals primarily emitted from the endoplasmic reticulum.

Differential Effects of Bcl-2 on Cell Death Triggered under ATP-Depleting Conditions

“…A decrease of ⌬⌿ m can occur in a reversible manner without any cytochrome c release and cell death [47][48][49]. ATP depletion alone does not necessarily lead to depolarization of the mitochondria [34].…”

The permeability transition and BCL-2 family proteins in apoptosis: co-conspirators or independent agents?

“…Furthermore, short PTP opening is likely to mediate fast release of Ca 2 þ from mitochondria. 28,38,[40][41][42] As Ca 2 þ is the most important cellular permissive factor for PTP opening, the close coupling of mitochondrial and ER Ca 2 þ levels may provide an initial level of coordination between the action of the PTP and BCL-2 family members. A number of studies have demonstrated that members of the BCL-2 family reside not only in the OMM but also in the ER where they have opposing actions in regulating the transfer of ER Ca 2 þ to mitochondria; antiapoptotic members reduce ER Ca 2 þ and pro-apoptotic members promote Ca 2 þ mobilization from the ER to mitochondria during apoptosis, perhaps by regulating of the activity of the ER inositol trisphosphate receptor.…”

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

“…The PT pore participates in the regulation of matrix Ca 2+ , pH, DC m , and volume and functions as a Ca 2+ -, voltage-, pH-, and redox-gated channel with several levels of conductance and little if any ion selectivity (Bernardi and Petronilli, 1996;Ichas et al, 1997;Zoratti and SzaboÁ , 1995). PT pores are multiprotein complexes formed at the contact site between the mitochondrial inner and outer membranes, exactly at the same localization at which Bax, Bcl-2 and Bcl-X L are particularly abundant.…”

“…Unfortunately, the conclusion that cytochrome c is released early, before the DC m disruption occurs, is mostly based on experiments involving rhodamine 123, which is not always appropriate for DC m quantitation (Metivier et al, 1998). In any case, since the PT pore can function at di erent states of conductance and reversibility (Kinnally et al, 1996;Zoratti and SzaboÁ , 1995), it is possible that the function of the respiratory chain restores the DC m in conditions in which the PT is¯ickering (Ichas et al, 1997), although PT pore opening remains the primum movens for an increase in mitochondrial volume and cytochrome c release. In accord with this possibility, it has been found that a PT-mediated reversible loss of the DC m accompanied by cytochrome c release precedes glutamate-induced neuronal apoptosis (Ankarcrona et al, 1995).…”