Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control

Glytsou, Christina; Calvo, Enrique; Cogliati, Sara; Mehrotra, Arpit; Anastasia, Irene; Rigoni, Giovanni; Raimondi, Andrea; Shintani, Norihito; Loureiro, Marta Bruno; Vázquez, Jesús; Pellegrini, Luca; Enrı́quez, José Antonio; Scorrano, Luca; Soriano, María Eugenia

doi:10.1016/j.celrep.2016.11.049

Cited by 132 publications

(156 citation statements)

References 47 publications

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“…Notably, a loss of OPA1 leads to opening of the CJ allowing Ca 2+ influx from the intermembrane space into the inner cristae. Such Ca 2+ accumulation inside the cristae is known to accompany altered cristae shape [12, 14], impair respiratory chain super-complexes and respiration [6], and increase the susceptibility of the organelle for apoptotic stimuli [11]. Our present data using a targeted genetically encoded fluorescent protein together with MTG revealed that the dynamics of the CM but not the IBM was strongly reduced by depletion of OPA1.…”

Section: Discussionmentioning

confidence: 53%

“…1c). Considering that a knock-down of OPA1 results in a broadening of the CJ [11, 14], our data suggest that cristae dynamics is reduced under conditions of widened CJ (Fig. 1d).…”

Section: Resultsmentioning

confidence: 93%

“…The critical importance of an optimized mitochondrial ultrastructure for the organelle’s fate is exemplarily illustrated by OPA1, which determines the width of the CM due to its oligomerization of membrane-bound and soluble forms [11, 14, 35]. Notably, a loss of OPA1 leads to opening of the CJ allowing Ca 2+ influx from the intermembrane space into the inner cristae.…”

Section: Discussionmentioning

confidence: 99%

“…The dynamin-related GTPase OPA1 (Optical Atrophy 1) is located to the IMM and controls the diameter of CJ, thus being crucially involved in cytochrome c release and, hence, the initiation of apoptosis [39]. Notably, it was shown that the oligomerization of membrane-bound and the soluble forms of OPA1 in the inner mitochondrial space (IMS) correlates with the tightness of CJ [11, 14, 35]. Accordingly, a depletion of OPA1 leads to fragmentation of mitochondria and also evokes drastic disorganization of the cristae [1, 5, 22] and increased susceptibility to apoptosis [24].…”

Section: Introductionmentioning

confidence: 99%

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Intracellular Ca2+ release decelerates mitochondrial cristae dynamics within the junctions to the endoplasmic reticulum

Gottschalk

Klec

Waldeck-Weiermair

et al. 2018

Pflugers Arch - Eur J Physiol

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Mitochondria are multifunctional organelles that essentially contribute to cell signaling by sophisticated mechanisms of communications. Live cell imaging studies showed that mitochondria are dynamic and complex structures that form ramified networks by directed movements, fission, and fusion events. There is emerging evidence that the morphology of mitochondria determines cellular functions and vice versa. Several intracellular signaling pathways and messengers including Ca2+ dynamically influence the architecture of mitochondria. Because electron microscopy cannot be utilized for an assessment of dynamics of mitochondrial morphology in intact cells, most studies were performed using wide-field or laser confocal fluorescence microscopies that, due to limitations of their spatial resolution, do not allow investigating sub-mitochondrial structures. Accordingly, our understanding of the dynamics of substructures of mitochondria is quite limited. Here, we present a robust super-resolution method to quantify the dynamics of mitochondrial cristae, the main substructures of the inner mitochondrial membrane, exploiting structured illumination microscopy (SIM). We observed that knockdown of the dynamin-like 120-kDa protein, which is encoded by the OPA1 gene, specifically reduces the dynamics of the mitochondrial cristae membranes (CM), while the inner boundary membrane (IBM) remained flexible. We further used dual color SIM to quantify the dynamics of CM in the junction between mitochondria and the endoplasmic reticulum (ER; mitochondrial associated membranes, MAMs). Intracellular Ca2+ release spatially reduced CM-dynamics in MAMs. Moreover, CM-dynamics was independent from matrix Ca2+ signal. Our data suggest that local Ca2+ signals specifically control CM-dynamics and structure to facilitate a well-balanced functional (Ca2+) interplay between mitochondria and the ER.

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Section: Discussionmentioning

confidence: 53%

“…1c). Considering that a knock-down of OPA1 results in a broadening of the CJ [11, 14], our data suggest that cristae dynamics is reduced under conditions of widened CJ (Fig. 1d).…”

Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intracellular Ca2+ release decelerates mitochondrial cristae dynamics within the junctions to the endoplasmic reticulum

Gottschalk

Klec

Waldeck-Weiermair

et al. 2018

Pflugers Arch - Eur J Physiol

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“…OPA1 regulates crista junction number and stability and is the sole regulator of cristae junction width (45). Our findings show that TIA proteins posttranscriptionally downregulate OPA1 gene expression through direct regulatory events linked to splicing and translation of OPA1 and through the functional forms of OPA1 associated with proteolytic processing mediated by OMA1.…”

Section: Discussionmentioning

confidence: 67%

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

Carrascoso

Alcalde

Sánchez-Jiménez

et al. 2017

Molecular and Cellular Biology

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Mitochondria undergo frequent morphological changes to control their function. We show here that T-cell intracellular antigens (TIA1b/TIARb) and Hu antigen R (HuR) have antagonistic roles in mitochondrial function by modulating the expression of mitochondrial shaping proteins. Expression of TIA1b/TIARb alters the mitochondrial dynamic network by enhancing fission and clustering, which is accompanied by a decrease in respiration. In contrast, HuR expression promotes fusion and cristae remodeling and increases respiratory activity. Mechanistically, TIA proteins downregulate the expression of optic atrophy 1 (OPA1) protein via switching of the splicing patterns of OPA1 to facilitate the production of OPA1 variant 5 (OPA1v5). Conversely, HuR enhances the expression of OPA1 mRNA isoforms through increasing steady-state levels and targeting translational efficiency at the 3= untranslated region. Knockdown of TIA1/ TIAR or HuR partially reversed the expression profile of OPA1, whereas knockdown of OPA1 or overexpression of OPA1v5 provoked mitochondrial clustering. Middle-term expression of TIA1b/TIARb triggers reactive oxygen species production and mitochondrial DNA damage, which is accompanied by mitophagy, autophagy, and apoptosis. In contrast, HuR expression promotes mitochondrion-dependent cell proliferation. Collectively, these results provide molecular insights into the antagonistic functions of TIA1b/TIARb and HuR in mitochondrial activity dynamics and suggest that their balance might contribute to mitochondrial physiopathology.

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MICOS and the mitochondrial inner membrane morphology – when things get out of shape

2021

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Mitochondria play a key role in cellular signalling, metabolism and energetics. Proper architecture and remodelling of the inner mitochondrial membrane are essential for efficient respiration, apoptosis and quality control in the cell. Several protein complexes including mitochondrial contact site and cristae organising system (MICOS), F 1 F O -ATP synthase, and Optic Atrophy 1 (OPA1), facilitate formation, maintenance and stability of cristae membranes. MICOS, the F 1 F O -ATP synthase, OPA1 and inner membrane phospholipids such as cardiolipin and phosphatidylethanolamine interact with each other to organise the inner membrane ultrastructure and remodel cristae in response to the cell's demands. Functional alterations in these proteins or in the biosynthesis pathway of cardiolipin and phosphatidylethanolamine result in an aberrant inner membrane architecture and impair mitochondrial function. Mitochondrial dysfunction and abnormalities hallmark several human conditions and diseases including neurodegeneration, cardiomyopathies and diabetes mellitus. Yet, they have long been regarded as secondary pathological effects. This review discusses emerging evidence of a direct relationship between protein-and lipid-dependent regulation of the inner mitochondrial membrane morphology and diseases such as fatal encephalopathy, Leigh syndrome, Parkinson's disease, and cancer.

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Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control

Cited by 132 publications

References 47 publications

Intracellular Ca2+ release decelerates mitochondrial cristae dynamics within the junctions to the endoplasmic reticulum

Intracellular Ca2+ release decelerates mitochondrial cristae dynamics within the junctions to the endoplasmic reticulum

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

MICOS and the mitochondrial inner membrane morphology – when things get out of shape

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