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International Journal of Biological... Apr 2023Mitochondria are centers of energy metabolism. The mitochondrial network is shaped by mitochondrial dynamics, including the processes of mitochondrial fission and fusion... (Review)
Review
Mitochondria are centers of energy metabolism. The mitochondrial network is shaped by mitochondrial dynamics, including the processes of mitochondrial fission and fusion and cristae remodeling. The cristae folded by the inner mitochondrial membrane are sites of the mitochondrial oxidative phosphorylation (OXPHOS) system. However, the factors and their coordinated interplay in cristae remodeling and linked human diseases have not been fully demonstrated. In this review, we focus on key regulators of cristae structure, including the mitochondrial contact site and cristae organizing system, optic atrophy-1, mitochondrial calcium uniporter, and ATP synthase, which function in the dynamic remodeling of cristae. We summarized their contribution to sustaining functional cristae structure and abnormal cristae morphology, including a decreased number of cristae, enlarged cristae junctions, and cristae as concentric ring structures. These abnormalities directly impact cellular respiration and are caused by dysfunction or deletion of these regulators in diseases such as Parkinson's disease, Leigh syndrome, and dominant optic atrophy. Identifying the important regulators of cristae morphology and understanding their role in sustaining mitochondrial morphology could be applied to explore the pathologies of diseases and to develop relevant therapeutic tools.
Topics: Humans; Mitochondrial Membranes; Mitochondria; Oxidative Phosphorylation; Energy Metabolism; Mitochondrial Proteins
PubMed: 36812974
DOI: 10.1016/j.ijbiomac.2023.123755 -
Antioxidants & Redox Signaling Oct 2023The architecture of the mitochondrial network and cristae critically impact cell differentiation and identity. Cells undergoing metabolic reprogramming to aerobic... (Review)
Review
The architecture of the mitochondrial network and cristae critically impact cell differentiation and identity. Cells undergoing metabolic reprogramming to aerobic glycolysis (Warburg effect), such as immune cells, stem cells, and cancer cells, go through controlled modifications in mitochondrial architecture, which is critical for achieving the resulting cellular phenotype. Recent studies in immunometabolism have shown that the manipulation of mitochondrial network dynamics and cristae shape directly affects T cell phenotype and macrophage polarization through altering energy metabolism. Similar manipulations also alter the specific metabolic phenotypes that accompany somatic reprogramming, stem cell differentiation, and cancer cells. The modulation of oxidative phosphorylation activity, accompanied by changes in metabolite signaling, reactive oxygen species generation, and adenosine triphosphate levels, is the shared underlying mechanism. The plasticity of mitochondrial architecture is particularly vital for metabolic reprogramming. Consequently, failure to adapt the appropriate mitochondrial morphology often compromises the differentiation and identity of the cell. Immune, stem, and tumor cells exhibit striking similarities in their coordination of mitochondrial morphology with metabolic pathways. However, although many general unifying principles can be observed, their validity is not absolute, and the mechanistic links thus need to be further explored. Better knowledge of the molecular mechanisms involved and their relationships to both mitochondrial network and cristae morphology will not only further deepen our understanding of energy metabolism but may also contribute to improved therapeutic manipulation of cell viability, differentiation, proliferation, and identity in many different cell types. 39, 684-707.
Topics: Mitochondrial Dynamics; Mitochondria; Energy Metabolism; Oxidative Phosphorylation; Metabolic Networks and Pathways; Glycolysis; Cellular Reprogramming
PubMed: 37212238
DOI: 10.1089/ars.2023.0268 -
Cell Sep 2013Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae....
Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae. Here, we investigate the relationship between respiratory function and mitochondrial ultrastructure and provide evidence that cristae shape determines the assembly and stability of RCS and hence mitochondrial respiratory efficiency. Genetic and apoptotic manipulations of cristae structure affect assembly and activity of RCS in vitro and in vivo, independently of changes to mitochondrial protein synthesis or apoptotic outer mitochondrial membrane permeabilization. We demonstrate that, accordingly, the efficiency of mitochondria-dependent cell growth depends on cristae shape. Thus, RCS assembly emerges as a link between membrane morphology and function.
Topics: Amino Acid Sequence; Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Cell Respiration; Electron Transport; GTP Phosphohydrolases; Humans; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Membranes; Molecular Sequence Data; Multiprotein Complexes; Sequence Alignment
PubMed: 24055366
DOI: 10.1016/j.cell.2013.08.032 -
Annual Review of Physiology 2016Permanent residency in the eukaryotic cell pressured the prokaryotic mitochondrial ancestor to strategize for intracellular living. Mitochondria are able to autonomously... (Review)
Review
Permanent residency in the eukaryotic cell pressured the prokaryotic mitochondrial ancestor to strategize for intracellular living. Mitochondria are able to autonomously integrate and respond to cellular cues and demands by remodeling their morphology. These processes define mitochondrial dynamics and inextricably link the fate of the mitochondrion and that of the host eukaryote, as exemplified by the human diseases that result from mutations in mitochondrial dynamics proteins. In this review, we delineate the architecture of mitochondria and define the mechanisms by which they modify their shape. Key players in these mechanisms are discussed, along with their role in manipulating mitochondrial morphology during cellular action and development. Throughout, we highlight the evolutionary context in which mitochondrial dynamics emerged and consider unanswered questions whose dissection might lead to mitochondrial morphology-based therapies.
Topics: Animals; Humans; Membrane Fusion; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins
PubMed: 26667075
DOI: 10.1146/annurev-physiol-021115-105011 -
Cell Jul 2006Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and...
Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and remodeling of the cristae. Here we provide evidence that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion. OPA1 does not interfere with activation of the mitochondrial "gatekeepers" BAX and BAK, but it controls the shape of mitochondrial cristae, keeping their junctions tight during apoptosis. Tightness of cristae junctions correlates with oligomerization of two forms of OPA1, a soluble, intermembrane space and an integral inner membrane one. The proapoptotic BCL-2 family member BID, which widens cristae junctions, also disrupts OPA1 oligomers. Thus, OPA1 has genetically and molecularly distinct functions in mitochondrial fusion and in cristae remodeling during apoptosis.
Topics: Animals; Apoptosis; Cell Line; GTP Phosphohydrolases; Membrane Fusion; Mice; Mice, Knockout; Mitochondria; Mitochondrial Membranes; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tight Junctions; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 16839885
DOI: 10.1016/j.cell.2006.06.025 -
Molecular Biology and Evolution Apr 2017Mitochondria are the respiratory organelles of eukaryotes and their evolutionary history is deeply intertwined with that of eukaryotes. The compartmentalization of... (Review)
Review
Mitochondria are the respiratory organelles of eukaryotes and their evolutionary history is deeply intertwined with that of eukaryotes. The compartmentalization of respiration in mitochondria occurs within cristae, whose evolutionary origin has remained unclear. Recent discoveries, however, have revived the old notion that mitochondrial cristae could have had a pre-endosymbiotic origin. Mitochondrial cristae are likely homologous to the intracytoplasmic membranes (ICMs) used by diverse alphaproteobacteria for harnessing energy. Because the Mitochondrial Contact site and Cristae Organizing System (MICOS) that controls the development of cristae evolved from a simplified version that is phylogenetically restricted to Alphaproteobacteria (alphaMICOS), ICMs most probably transformed into cristae during the endosymbiotic origin of mitochondria. This inference is supported by the sequence and structural similarities between MICOS and alphaMICOS, and the expression pattern and cellular localization of alphaMICOS. Given that cristae and ICMs develop similarly, alphaMICOS likely functions analogously to mitochondrial MICOS by culminating ICM development with the creation of tubular connections and membrane contact sites at the alphaproteobacterial envelope. Mitochondria thus inherited a pre-existing ultrastructure adapted to efficient energy transduction from their alphaproteobacterial ancestors. The widespread nature of purple bacteria among alphaproteobacteria raises the possibility that cristae evolved from photosynthetic ICMs.
Topics: Alphaproteobacteria; Biological Evolution; Evolution, Molecular; Membrane Proteins; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Phylogeny; Protein Binding; Symbiosis
PubMed: 28087774
DOI: 10.1093/molbev/msw298 -
Biochimica Et Biophysica Acta.... Jun 2017A fundamental question in cell biology, under investigation for over six decades, is the structural organization of mitochondrial cristae. Long known to harbor electron... (Review)
Review
A fundamental question in cell biology, under investigation for over six decades, is the structural organization of mitochondrial cristae. Long known to harbor electron transport chain proteins, crista membrane integrity is key to establishment of the proton gradient that drives oxidative phosphorylation. Visualization of cristae morphology by electron microscopy/tomography has provided evidence that cristae are tube-like extensions of the mitochondrial inner membrane (IM) that project into the matrix space. Reconciling ultrastructural data with the lipid composition of the IM provides support for a continuously curved cylindrical bilayer capped by a dome-shaped tip. Strain imposed by the degree of curvature is relieved by an asymmetric distribution of phospholipids in monolayer leaflets that comprise cristae membranes. The signature mitochondrial lipid, cardiolipin (~18% of IM phospholipid mass), and phosphatidylethanolamine (34%) segregate to the negatively curved monolayer leaflet facing the crista lumen while the opposing, positively curved, matrix-facing monolayer leaflet contains predominantly phosphatidylcholine. Associated with cristae are numerous proteins that function in distinctive ways to establish and/or maintain their lipid repertoire and structural integrity. By combining unique lipid components with a set of protein modulators, crista membranes adopt and maintain their characteristic morphological and functional properties. Once established, cristae ultrastructure has a direct impact on oxidative phosphorylation, apoptosis, fusion/fission as well as diseases of compromised energy metabolism.
Topics: Acyltransferases; Blood Proteins; Cardiolipins; GTP Phosphohydrolases; Gene Expression Regulation; Humans; Membrane Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Oxidative Phosphorylation; Phosphatidylcholines; Phosphatidylethanolamines; Prohibitins; Repressor Proteins; Transcription Factors
PubMed: 28336315
DOI: 10.1016/j.bbamem.2017.03.013 -
Mitochondrion Nov 2019Type 2 diabetes progression stems from dysfunction of β-cells, besides the peripheral insulin resistance. Mitochondria as glucose sensor and regulation center are... (Review)
Review
Type 2 diabetes progression stems from dysfunction of β-cells, besides the peripheral insulin resistance. Mitochondria as glucose sensor and regulation center are impaired at various stages of this progression. Their biogenesis and functional impairment is reflected by altered morphology of the mitochondrial network and ultramorphology of cristae and mitochondrial DNA loci, termed nucleoids. Aspects of all above changes are reviewed here together with a brief introduction to proteins involved in mitochondrial network dynamics, cristae shaping, and mtDNA nucleoid structure and maintenance. Most frequently, pathology is reflected by the fragmentation of network, cristae inflation or absence and declining number of nucleoids.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes
PubMed: 31252091
DOI: 10.1016/j.mito.2019.06.007 -
Trends in Biochemical Sciences Mar 2016Mitochondrial cristae are dynamic bioenergetic compartments whose shape changes under different physiological conditions. Recent discoveries have unveiled the relation... (Review)
Review
Mitochondrial cristae are dynamic bioenergetic compartments whose shape changes under different physiological conditions. Recent discoveries have unveiled the relation between cristae shape and oxidative phosphorylation (OXPHOS) function, suggesting that membrane morphology modulates the organization and function of the OXPHOS system, with a direct impact on cellular metabolism. As a corollary, cristae-shaping proteins have emerged as potential modulators of mitochondrial bioenergetics, a concept confirmed by genetic experiments in mouse models of respiratory chain deficiency. Here, we review our knowledge of mitochondrial ultrastructural organization and how it impacts mitochondrial metabolism.
Topics: Mitochondria; Oxidative Phosphorylation
PubMed: 26857402
DOI: 10.1016/j.tibs.2016.01.001 -
Molecular Cell Mar 2023Mitochondria are not only central organelles in metabolism and energy conversion but are also platforms for cellular signaling cascades. Classically, the shape and... (Review)
Review
Mitochondria are not only central organelles in metabolism and energy conversion but are also platforms for cellular signaling cascades. Classically, the shape and ultrastructure of mitochondria were depicted as static. The discovery of morphological transitions during cell death and of conserved genes controlling mitochondrial fusion and fission contributed to establishing the concept that mitochondrial morphology and ultrastructure are dynamically regulated by mitochondria-shaping proteins. These finely tuned, dynamic changes in mitochondrial shape can in turn control mitochondrial function, and their alterations in human diseases suggest that this space can be explored for drug discovery. Here, we review the basic tenets and molecular mechanisms of mitochondrial morphology and ultrastructure, describing how they can coordinately define mitochondrial function.
Topics: Humans; Mitochondrial Dynamics; Mitochondria; Cell Death; Signal Transduction; Mitochondrial Proteins
PubMed: 36889315
DOI: 10.1016/j.molcel.2023.02.012