A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

Abstract

Mitochondria are crucial amplifiers of death signals. They release cytochrome c and other pro-apoptotic factors required to fully activate effector caspases. This release is accompanied by fragmentation of the mitochondrial reticulum and by remodelling of the internal structure of the organelle. Here we review data supporting the existence of a regulatory network in the inner mitochondrial membrane that includes optic atrophy 1 (Opa1), a dynamin-related protein, and presenilin-associated rhomboidlike (Parl), a rhomboid protease. Opa1 regulates remodelling of the cristae independent of its effect on fusion. Cristae remodelling conversely requires Parl, which participates in the production of a soluble form of Opa1 retrieved together with the integral membrane one in oligomers that are disrupted early during apoptosis. Parl itself is regulated by proteolysis to generate a cleaved form, which in turn modulates the shape of the mitochondrial reticulum. Cleavage of Parl depends on its phosphorylation state around the cleavage site, implicating mitochondrial kinases and phosphatases in the regulation of mitochondrial shape.

Autocatalytic Processing of m-AAA Protease Subunits in Mitochondria

“…It remains to be determined whether this reflects different substrate specificities of mouse and yeast MPP used in our experiments, or whether another, yet to be identified peptidase is involved in Afg3l2 processing. The rhomboid protease PARL has been discussed as a candidate processing enzyme for m-AAA protease subunits (Pellegrini and Scorrano, 2007). However, mitochondrial import experiments in vitro and experiments in PARL-deficient MEFs did not provide any evidence for a requirement of PARL for maturation, regardless of the presence of Afg3l1 and Afg3l2 (Supplemental Figure S4).…”

Multistep and multitask Bax activation

“…Accordingly, at least three events must take place to allow export from mitochondria (Pellegrini and Scorrano, 2007). Cytochrome c must be freed from cardiolipin anchorage; cristae junctions must be opened; and Bax pores must form through which cytochrome c may translocate to cytosol.…”

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

“…Chief among these is Opa1. A detailed discussion of this and other contributors to cristae remodeling and/or disruption of the cytochrome c/cardiolipin interaction during apoptosis is beyond the scope of this review, but can be found in the following papers: (Bayir et al, 2006;Garrido et al, 2006;HeathEngel and Shore, 2006;Gonzalvez and Gottlieb, 2007;Orrenius, 2007;Ott et al, 2007;Pellegrini and Scorrano, 2007) Apoptosis and ER Ca 2 þ release: BAX, BAK and antiapoptotic BCL-2 family members Regulation of apoptosis by BCL-2 family members at the ER is largely dependent on their ability to modulate ER Ca 2 þ signaling. Ca 2 þ signaling during apoptosis is enhanced by the proapoptotic family members BAX/ BAK and dampened by the antiapoptotic BCL-2 and BCL-xL proteins.…”