The Opa1-Dependent Mitochondrial Cristae Remodeling Pathway Controls Atrophic, Apoptotic, and Ischemic Tissue Damage

Abstract

SummaryMitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo.

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

“…[24][25][26][27] Mitochondrial dysfunction can weaken a cell's capacity to respond to a range of metabolic processes, including additional oxidative stress and fatty acid overload, and can contribute to progressive disease. 3,28 A transgenic mouse model has shown that mitochondrial dysfunction in podocytes induced by TGF-b signaling preceded the manifestation of segmental glomerulosclerosis.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Oligomerization of Opa-1, together with ATP synthase subunits e and g [10], Mitofilin and possibly every component of the "mitochondrial contact site and cristae organizing system" (MICOS) complex [11], also regulates the width of cristae junctions, connectionsites between the IMM and the cristae, where OXPHOS complexes and cytocrome-C (cytC) are localized. Thus, Opa-1 controls cytC release from the cristae during apoptosis (see Section 2.1 for details) [12,13]. Moreover, Opa-1 is a regulator of the mitochondrial quality control.…”

Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria

“…Rather, our results indicate that stabilization of L-OPA1 and mitochondrial fusion ensures neuronal survival in the absence of PHB2, demonstrating a crucial role of OMA1 in neuronal survival in vivo. In light of our observations, it is conceivable that the protective effect of OPA1 overexpression in various mitochondrial disease mouse models Varanita et al, 2015) can be attributed to L-OPA1 only, which drives fusion and can support cell survival independently of cristae morphogenesis.…”

“…Loss of OPA1 impairs mitochondrial fusion, disturbs cristae morphogenesis, and increases the apoptotic sensitivity of cells (Olichon et al, 2003;Cipolat et al, 2004;Meeusen et al, 2006). On the other hand, overexpression of OPA1 protects against apoptotic and ischemic tissue damage and ameliorates phenotypes of mitochondrial disease mouse models Civiletto et al, 2015;Varanita et al, 2015). OPA1 function is regulated by proteolytic cleavage at sites S1 and S2, which results in the balanced accumulation of noncleaved, long (L-OPA1) and cleaved, short (S-OPA1) OPA1 forms (Ishihara et al, 2006;Griparic et al, 2007).…”