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Cell Reports Sep 2022Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the...
Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.
Topics: Endoplasmic Reticulum; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Phosphatidylserines
PubMed: 36130504
DOI: 10.1016/j.celrep.2022.111364 -
Autophagy Sep 2023Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome...
Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them toward elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.
Topics: DNA, Mitochondrial; Mitophagy; Autophagy; Mitochondria; Endosomes; Mitochondrial Proteins
PubMed: 36691806
DOI: 10.1080/15548627.2023.2170959 -
Biochimica Et Biophysica Acta.... Apr 2017The elaborate membrane architecture of mitochondria is a prerequisite for efficient respiration and ATP generation. The cristae membranes, invaginations of the inner... (Review)
Review
The elaborate membrane architecture of mitochondria is a prerequisite for efficient respiration and ATP generation. The cristae membranes, invaginations of the inner mitochondrial membrane, represent a specialized compartment that harbors the complexes of the respiratory chain and the FF-ATP synthase. Crista junctions form narrow openings that connect the cristae membranes to the inner boundary membrane. The mitochondrial contact site and cristae organizing system (MICOS) is located at crista junctions where it stabilizes membrane curvature and forms contact sites between the mitochondrial inner and outer membranes. MICOS is a large machinery, consisting of two dynamic subcomplexes that are anchored in the inner membrane and expose domains to the intermembrane space. The functions of MICOS in mitochondrial membrane architecture and biogenesis are influenced by numerous interaction partners and the phospholipid environment.
Topics: Animals; DNA, Mitochondrial; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Phospholipids; Protein Binding; Proton-Translocating ATPases; Saccharomyces cerevisiae; Signal Transduction; Species Specificity
PubMed: 27614134
DOI: 10.1016/j.bbamcr.2016.05.020 -
FASEB Journal : Official Publication of... Jan 2022Mitochondrial dysfunction or loss of homeostasis is a central hallmark of many human diseases. Mitochondrial homeostasis is mediated by multiple quality control...
Mitochondrial dysfunction or loss of homeostasis is a central hallmark of many human diseases. Mitochondrial homeostasis is mediated by multiple quality control mechanisms including mitophagy, a form of selective autophagy that recycles terminally ill or dysfunctional mitochondria in order to preserve mitochondrial integrity. Our prior studies have shown that members of the insulin-like growth factor (IGF) family localize to the mitochondria and may play important roles in mediating mitochondrial health in the corneal epithelium, an integral tissue that is required for the maintenance of optical transparency and vision. Importantly, the IGF-binding protein-3, IGFBP-3, is secreted by corneal epithelial cells in response to stress and functions to mediate intracellular receptor trafficking in this cell type. In this study, we demonstrate a novel role for IGFBP-3 in mitochondrial homeostasis through regulation of the short isoform (s)BNIP3L/NIX mitophagy receptor in corneal epithelial cells and extend this finding to non-ocular epithelial cells. We further show that IGFBP-3-mediated control of mitochondrial homeostasis is associated with alterations in lamellar cristae morphology and mitochondrial dynamics. Interestingly, both loss and gain of function of IGFBP-3 drive an increase in mitochondrial respiration. This increase in respiration is associated with nuclear accumulation of IGFBP-3. Taken together, these findings support a novel role for IGFBP-3 as a key mediator of mitochondrial health in mucosal epithelia through the regulation of mitophagy and mitochondrial morphology.
Topics: Cell Line, Transformed; Epithelium, Corneal; Homeostasis; Humans; Insulin-Like Growth Factor Binding Protein 3; Membrane Proteins; Mitochondria; Mitophagy; Mucous Membrane; Proto-Oncogene Proteins; Tumor Suppressor Proteins
PubMed: 34918377
DOI: 10.1096/fj.202100710RR -
Biochimica Et Biophysica Acta.... Jan 2017Among mitochondrial lipids, cardiolipin occupies a unique place. It is the only phospholipid that is specific to mitochondria and although it is merely a minor... (Review)
Review
Among mitochondrial lipids, cardiolipin occupies a unique place. It is the only phospholipid that is specific to mitochondria and although it is merely a minor component, accounting for 10-20% of the total phospholipid content, cardiolipin plays an important role in the molecular organization, and thus the function of the cristae. This review covers the formation of cardiolipin, a phospholipid dimer containing two phosphatidyl residues, and its assembly into mitochondrial membranes. While a large body of literature exists on this topic, the review focuses on papers that appeared in the past three years. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Topics: Animals; Cardiolipins; Humans; Mitochondria; Mitochondrial Membranes; Phospholipids; Protein Biosynthesis
PubMed: 27556952
DOI: 10.1016/j.bbalip.2016.08.010 -
Trends in Biochemical Sciences Apr 2024Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular... (Review)
Review
Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g., donuts, megamitochondria (MGs), and nanotunnels] and crista dynamics. This review explores the significance of dynamic alterations in mitochondrial morphology and regulators of mitochondrial and cristae shape. We focus on studies across tissue types and also describe new microscopy techniques for detecting mitochondrial morphologies both in vivo and in vitro that can improve understanding of mitochondrial structure. We highlight the potential therapeutic benefits of regulating mitochondrial morphology and discuss prospective avenues to restore mitochondrial bioenergetics to manage diseases related to mitochondrial dysfunction.
Topics: Prospective Studies; Mitochondria; Mitochondrial Membranes; Energy Metabolism
PubMed: 38402097
DOI: 10.1016/j.tibs.2024.01.011 -
STAR Protocols Mar 2023Since changes in mitochondrial morphology regulate key functions of stem cells, it is important to assess their structure under physiological and pathophysiological...
Since changes in mitochondrial morphology regulate key functions of stem cells, it is important to assess their structure under physiological and pathophysiological conditions. Here, we present techniques optimized in rare adult muscle stem cells (MuSCs). For evaluating mitochondrial length and volume within a compact cytoplasmic area in MuSCs on intact myofibers, we describe steps for mitochondrial staining, imaging, and quantification. For evaluating mitochondrial ultrastructure in small cell numbers, we describe steps for agarose embedding and quantification by TEM. For complete details on generation and use of this protocol, please refer to Baker et al. (2022)..
Topics: Animals; Mice; Mitochondria; Mitochondrial Membranes; Adult Stem Cells; Cytoplasm; Stem Cells
PubMed: 36853728
DOI: 10.1016/j.xpro.2023.102107 -
Mitochondrion Jul 2023As the cell's energy factory and metabolic hub, mitochondria are critical for ATP synthesis to maintain cellular function. Mitochondria are highly dynamic organelles... (Review)
Review
As the cell's energy factory and metabolic hub, mitochondria are critical for ATP synthesis to maintain cellular function. Mitochondria are highly dynamic organelles that continuously undergo fusion and fission to alter their size, shape, and position, with mitochondrial fusion and fission being interdependent to maintain the balance of mitochondrial morphological changes. However, in response to metabolic and functional damage, mitochondria can grow in size, resulting in a form of abnormal mitochondrial morphology known as megamitochondria. Megamitochondria are characterized by their considerably larger size, pale matrix, and marginal cristae structure and have been observed in various human diseases. In energy-intensive cells like hepatocytes or cardiomyocytes, the pathological process can lead to the growth of megamitochondria, which can further cause metabolic disorders, cell damage and aggravates the progression of the disease. Nonetheless, megamitochondria can also form in response to short-term environmental stimulation as a compensatory mechanism to support cell survival. However, extended stimulation can reverse the benefits of megamitochondria leading to adverse effects. In this review, we will focus on the findings of the different roles of megamitochondria, and their link to disease development to identify promising clinical therapeutic targets.
Topics: Humans; Mitochondrial Swelling; Mitochondria; Metabolic Diseases; Hepatocytes; Mitochondrial Membranes; Mitochondrial Dynamics
PubMed: 37276954
DOI: 10.1016/j.mito.2023.06.001 -
Journal of Cellular Physiology Apr 2019The identification of the mitochondrial contact site and cristae organizing system (MICOS) in the inner mitochondrial membrane shed light on the intricate components... (Review)
Review
The identification of the mitochondrial contact site and cristae organizing system (MICOS) in the inner mitochondrial membrane shed light on the intricate components necessary for mitochondria to form their signature cristae in which many protein complexes including the electron transport chain are localized. Mic60/mitofilin has been described as the core component for the assembly and maintenance of MICOS, thus controlling cristae morphology, protein transport, mitochondrial DNA transcription, as well as connecting the inner and outer mitochondrial membranes. Although Mic60 homologs are present in many species, mammalian Mic60 is only recently gaining attention as a critical player in several organ systems and diseases with mitochondrial-defect origins. In this review, we summarize what is currently known about the ever-expanding role of Mic60 in mammals, and highlight some new studies pushing the field of mitochondrial cristae organization towards potentially new and exciting therapies targeting this protein.
Topics: Animals; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Mitochondrial Proteins; Muscle Proteins; Signal Transduction
PubMed: 30259514
DOI: 10.1002/jcp.27314 -
FEBS Letters Apr 2021Mitochondria play a key role in cellular signalling, metabolism and energetics. Proper architecture and remodelling of the inner mitochondrial membrane are essential for... (Review)
Review
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 organizing system (MICOS), F F -ATP synthase, and Optic Atrophy 1 (OPA1), facilitate formation, maintenance and stability of cristae membranes. MICOS, the F F -ATP synthase, OPA1 and inner membrane phospholipids such as cardiolipin and phosphatidylethanolamine interact with each other to organize the inner membrane ultra-structure 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.
Topics: Apoptosis; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Mitochondrial Proteins
PubMed: 33837538
DOI: 10.1002/1873-3468.14089