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

Abstract

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.

Emerging Roles of the MICOS Complex in Cristae Dynamics and Biogenesis

“…The variety of functions that MICOS could perform, apart from cristae biogenesis, could be attributed to its interaction with the proteins mentioned. These include protein import, apoptosis, mitophagy, mitochondrial DNA organization, translation, transport and PL biogenesis [46,47]. Owing to its importance, alterations in the levels or modifications of MICOS subunits are found in many pathologies such as cancer, diabetes, neurodegenerative and cardiac diseases [12,48,49].…”

Mitochondrial Membrane Remodeling

“…Mitochondrial membrane composition and architecture are essential for mitochondrial function and characterizing abnormal mitochondrial structural features may provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Dysregulation of factors involved in mitochondrial membrane morphogenesis, such as defects in relevant protein complexes or phospholipid synthetic enzymes that result in aberrant cristae architecture have been linked to an increasing number of human diseases including neurodegeneration, cardiomyopathies, diabetes mellitus, aging, and cancer ( Zong et al, 2016 ; Li et al, 2020 ; Mukherjee et al, 2021 ). For example, mitochondrial ultrastructural defects are prominent in mitochondrial myopathy.…”

“…Fully understanding of the factors and pathways that regulate mitochondrial ultrastructure and mitochondrial lipid metabolism is required to design promising therapeutic strategies for eliminating dysfunctional mitochondria and renewing the pool of healthy organelles that are needed for the treatment of mitochondrial dysfunctional diseases. The link between protein- and lipid-dependent regulation of the inner mitochondrial membrane morphology and diseases has been summarized in recent reviews ( Chao de la Barca et al, 2016 ; Picard et al, 2016 ; Vincent et al, 2016 ; Falabella et al, 2021 ; Mukherjee et al, 2021 ).…”

“…Mitochondrial membrane structure, dynamics, and function closely rely on proteins and protein complexes associated with membranes, lipid organization, and the coordinated interplay between proteins and lipids in the mitochondrial membrane. Aberrant cristae ultrastructure, dynamics, and lipid composition cause many devastating human diseases, including neurodegenerative disorders, obesity, diabetes mellitus, muscular dystrophies, cardiomyopathies, and cancer ( Chan, 2006 ; Nunnari and Suomalainen, 2012 ; Friedman and Nunnari, 2014 ; Wai and Langer, 2016 ; Colina-Tenorio et al, 2020 ; Li et al, 2020 ; Mukherjee et al, 2021 ). Although the mitochondrial membrane architecture was discovered with the pioneering work of Palade and Sjöstrand in the 1950s ( Palade, 1952 ; Sjostrand, 1953 ), the molecular mechanisms underlying the formation of diverse mitochondrial membrane curvature have only been unraveled in part.…”

Dual role of Mic10 in mitochondrial cristae organization and ATP synthase-linked metabolic adaptation and respiratory growth

“…These invaginations of the inner mitochondrial membrane enable optimal efficiency of the respiratory chain both by their topology and by increasing the membrane surface. The organization and shaping of cristae are complex processes involving several machineries, and disruption of the inner membrane architecture is detrimental for mitochondrial physiology and associated with a variety of pathological conditions ( Cogliati et al., 2016 ; Colina-Tenorio et al., 2020 ; Eramo et al., 2020 ; Mukherjee et al., 2021 ). Two major cristae-shaping machineries were reported to function in an antagonistic manner with respect to cristae architecture, the mitochondrial contact site and cristae organizing system (MICOS), and the F 1 F o -ATP synthase ( Paumard et al., 2002 ; Rabl et al., 2009 ; Hoppins et al., 2011 ; Davies et al., 2012 ; Harner et al., 2016 ; Rampelt et al., 2017b ; Kojima et al., 2019 ; Stephan et al., 2020 ).…”