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Pathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed that Listeria monocytogenes infection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the presence of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response to L. monocytogenes infection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important for L. monocytogenes -dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used by L. monocytogenes to hijack mitochondria to optimize host infection. Mitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and nonphysiological cues. We previously showed that infection with the human bacterial pathogen Listeria monocytogenes elicits transient mitochondrial fission and a drop in mitochondrion-dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved in L. monocytogenes -induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficient L. monocytogenes . Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a posttranscriptional mechanism. We then showed that Mic10 is necessary for L. monocytogenes -induced mitochondrial network fragmentation and that it contributes to L. monocytogenes cellular infection independently of MICOS proteins Mic13, Mic26, and Mic27. In conclusion, investigation of L. monocytogenes infection allowed us to uncover a role for Mic10 in mitochondrial fission. IMPORTANCE Pathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed that Listeria monocytogenes infection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the presence of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response to L. monocytogenes infection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important for L. monocytogenes -dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used by L. monocytogenes to hijack mitochondria to optimize host infection.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's dementia. Mitochondrial dysfunction is involved in the pathology of PD. Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was identified as associated with autosomal dominant PD. However, the mechanism of CHCHD2 in PD remains unclear. Short hairpin RNA (ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma (SHSY5Y) and HeLa cells. Blue-native polyacrylamide gel electrophoresis (PAGE) and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system (MICOS). Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10. Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were used to examine the influence of CHCHD2 in vivo. We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model. Furthermore, we identified that CHCHD2 interacted with Mic10, and overexpression of CHCHD2 can protect against MPP + -induced MICOS impairment, while knockdown of CHCHD2 impaired the stability of MICOS. This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex, which contributes to protecting mitochondrial function in PD.

Structure and function of mitochondria are intimately linked. In a search for components that participate in building the elaborate architecture of this complex organelle we have identified Aim24, an inner membrane protein. Aim24 interacts with the MICOS complex that is required for the formation of crista junctions and contact sites between inner and outer membranes. Aim24 is necessary for the integrity of the MICOS complex, for normal respiratory growth and mitochondrial ultrastructure. Modification of MICOS subunits Mic12 or Mic26 by His-tags in the absence of Aim24 leads to complete loss of cristae and respiratory complexes. In addition, the level of tafazzin, a cardiolipin transacylase, is drastically reduced and the composition of cardiolipin is modified like in mutants lacking tafazzin. In conclusion, Aim24 by interacting with the MICOS complex plays a key role in mitochondrial architecture, composition and function. Respiration is vital to all living things because it is the process by which nutrients are converted into useful energy. Within our cells, organelles called mitochondria harness this energy and store it within molecules of ATP. This energy can then be released, when it is needed, by breaking down an ATP molecule into simpler chemicals. When viewed under an electron microscope, it can be seen that an individual mitochondrion has two membranes: a highly folded inner membrane, and an outer membrane that is fairly smooth. However, some of the genes, proteins and other molecules that determine the complex shapes of mitochondria have not been identified. Using a technique called mass spectrometry, a protein called Aim24 was previously shown to accumulate at the sites where the two membranes of a mitochondrion make contact with each other. Now, Harner et al. have discovered that Aim24 proteins are transported into mitochondria and embedded within the inner membranes. Aim24 is needed to assemble and maintain the stability of the protein complex that anchors the inner membrane to the outer membrane: mitochondria that lack the Aim24 protein have an irregular structure. Furthermore, Harner et al. showed that Aim24 is needed to form other protein complexes—also within the inner membrane—that work together to harness the energy that is released when nutrients are broken down, so that it can be stored as ATP. Cells that lack the Aim24 gene also showed changes in the kinds of molecules found within the membranes of the mitochondria. This work shows how difficult it can be to determine how the shapes of structures within cells, such as mitochondria, are controlled—as one protein can have many roles that cannot be easily teased apart. The on-going challenge is to uncover how different proteins, and other molecules in the membranes of mitochondria, interact to determine the structure, and consequently function, of the mitochondria in a cell.

Metals are key elements for the survival and normal development of humans but can also be toxic to cells when mishandled. In fact, even mild disruption of metal homeostasis causes a wide array of disorders. Many of the metals essential to normal physiology are required in mitochondria for enzymatic activities and for the formation of essential cofactors. Copper is required as a cofactor in the terminal electron transport chain complex cytochrome c oxidase, iron is required for the for the formation of iron-sulfur (Fe-S) clusters and heme, manganese is required for the prevention of oxidative stress production, and these are only a few examples of the critical roles that mitochondrial metals play. Even though the targets of these metals are known, we are still identifying transporters, investigating the roles of known transporters, and defining regulators of the transport process. Mitochondria are dynamic organelles whose content, structure and localization within the cell vary in different tissues and organisms. Our knowledge of the impact that alterations in mitochondrial physiology have on metal content and utilization in these organelles is very limited. The rates of fission and fusion, the ultrastructure of the organelle, and rates of mitophagy can all affect metal homeostasis and cofactor assembly. This review will focus of the emerging areas of overlap between metal homeostasis, cofactor assembly and the mitochondrial contact site and cristae organizing system (MICOS) that mediates multiple aspects of mitochondrial physiology. Importantly the MICOS complexes may allow for localization and organization of complexes not only involved in cristae formation and contact between the inner and outer mitochondrial membranes but also acts as hub for metal-related proteins to work in concert in cofactor assembly and homeostasis.

Background Mitochondrial DNA depletion syndrome (MTDPS) is part of a group of mitochondrial diseases characterized by a reduction in mitochondrial DNA copy number. Most MTDPS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism. Methods We performed the whole‐exome sequencing of a hepato‐encephalopathy patient with MTDPS and functional analyses to determine the clinical significance of the identified variant. Results Here, whole‐exome sequencing of a patient presenting with hepato‐encephalopathy and MTDPS identified a novel homozygous frameshift variant, c.13_29del (p.Trp6Profs*71) in MICOS13. MICOS13 (also known as QIL1, MIC13, or C19orf70) is a component of the MICOS complex, which plays crucial roles in the maintenance of cristae junctions at the mitochondrial inner membrane. We found loss of MICOS13 protein and fewer cristae structures in the mitochondria of fibroblasts derived from the patient. Stable expression of a wild‐type MICOS13 cDNA in the patients fibroblasts using a lentivirus system rescued mitochondrial respiratory chain complex deficiencies. Conclusion Our findings suggest that the novel c.13_29del (p.Trp6Profs*71) MICOS13 variant causes hepato‐encephalopathy with MTDPS. We propose that MICOS13 is classified as the cause of MTDPS. We performed the whole‐exome sequencing of the hepato‐encephalopathy patient with MTDPS. The functional analyses revealed the clinical significance of the identified variant.

The conserved MICOS complex functions as a primary determinant of mitochondrial inner membrane structure. We address the organization and functional roles of MICOS and identify two independent MICOS subcomplexes: Mic27/Mic10/Mic12, whose assembly is dependent on respiratory complexes and the mitochondrial lipid cardiolipin, and Mic60/Mic19, which assembles independent of these factors. Our data suggest that MICOS subcomplexes independently localize to cristae junctions and are connected via Mic19, which functions to regulate subcomplex distribution, and thus, potentially also cristae junction copy number. MICOS subunits have non-redundant functions as the absence of both MICOS subcomplexes results in more severe morphological and respiratory growth defects than deletion of single MICOS subunits or subcomplexes. Mitochondrial defects resulting from MICOS loss are caused by misdistribution of respiratory complexes in the inner membrane. Together, our data are consistent with a model where MICOS, mitochondrial lipids and respiratory complexes coordinately build a functional and correctly shaped mitochondrial inner membrane. Structures called mitochondria provide energy that cells need to live and grow. To do this, mitochondria convert energy stored within sugars and other carbon-rich compounds into the energy currency of cells, a molecule called adenosine triphosphate (called ATP for short). Defective mitochondria can cause cells to starve and also cause severe human diseases. A double membrane surrounds each mitochondrion. The outer membrane allows proteins and other substances to enter, while the inner membrane is elaborately folded and contains several groups of proteins—or complexes—including the respiratory complexes that generate ATP. Proper inner membrane folding is critically important. The membrane folds are held in place by structures called cristae junctions, which may also help to restrict proteins to particular areas of the inner membrane. A large inner membrane complex of proteins known as MICOS is important for organizing the inner membrane into folds, although exactly how it does so is not fully understood. MICOS consists of at least six different proteins, most of which are found across yeast and animal species. Friedman et al. have now analyzed how the MICOS complex assembles on the inner membrane in yeast cells using a combination of fluorescence and electron microscopy, proteomics and biochemistry. This revealed that in yeast, MICOS is made up of two independent sub-complexes bridged together by a protein called Mic19, which additional experiments suggest controls the number and positions of the cristae junctions that hold the folds of the inner membrane in place. As part of the approach to understand MICOS complex organization, Friedman et al. removed the six MICOS proteins from yeast cells. Inside these cells, the inner mitochondrial membrane was misfolded. Furthermore, the respiratory complexes did not work normally and as a consequence the cells were unable to grow normally, suggesting that the correct distribution of respiratory complexes in the inner membrane is important for ATP production and depends on MICOS. These results indicate that MICOS stabilizes the structure of the inner membrane and organizes it into an efficient energy-generating machine. In many human mitochondrial diseases, the inner membrane of mitochondria folds incorrectly, in similar ways to the misfolding seen in the yeast cells that did not contain the MICOS complex. Therefore, the MICOS complex may also influence how these diseases develop.

Mitochondria are organelles with a complex architecture. They are bounded by an envelope consisting of the outer membrane and the inner boundary membrane (IBM). Narrow crista junctions (CJs) link the IBM to the cristae. OMs and IBMs are firmly connected by contact sites (CS). The molecular nature of the CS remained unknown. Using quantitative high‐resolution mass spectrometry we identified a novel complex, the mi tochondrial co ntact s ite (MICOS) complex, formed by a set of mitochondrial membrane proteins that is essential for the formation of CS. MICOS is preferentially located at the CJs. Upon loss of one of the MICOS subunits, CJs disappear completely or are impaired, showing that CJs require the presence of CS to form a superstructure that links the IBM to the cristae. Loss of MICOS subunits results in loss of respiratory competence and altered inheritance of mitochondrial DNA. The outer and inner mitochondrial membranes are physically linked. Quantitative high resolution mass spectrometry now identifies the molecular nature of the Mitochondrial Contact Site complex (MICOS). MICOS is required for crista junctions formation, respiration and mitochondrial DNA inheritance.

Mitochondria are organelles of endosymbiotic origin, surrounded by two membranes. The inner membrane forms invaginations called cristae that enhance its surface and are important for mitochondrial function. A recently described mitochondrial contact site and cristae organizing system (MICOS) in the inner mitochondrial membrane is crucial for the formation and maintenance of cristae structure. The MICOS complex in human mitochondria exhibits specificities and greater complexity in comparison to the yeast system. Many subunits of this complex have been previously described, but several others and their function remain to be explored. This review will summarize our present knowledge about the human MICOS complex and its constituents, while discussing the future research perspectives in this exciting and important field.

The mitochondrial inner membrane organizing system (MINOS) is a conserved large hetero-oligomeric protein complex in the mitochondrial inner membrane, crucial for the maintenance of cristae morphology. MINOS has been suggested to represent the core of an extended protein network that controls mitochondrial function and structure, and has been linked to several human diseases. The spatial arrangement of MINOS within mitochondria is ill-defined, however. Using super-resolution stimulated emission depletion (STED) microscopy and immunogold electron microscopy, we determined the distribution of three known human MINOS subunits (mitofilin, MINOS1, and CHCHD3) in mammalian cells. Super-resolution microscopy revealed that all three subunits form similar clusters within mitochondria, and that MINOS is more abundant in mitochondria around the nucleus than in peripheral mitochondria. At the submitochondrial level, mitofilin, a core MINOS subunit, is preferentially localized at cristae junctions. In primary human fibroblasts, mitofilin labeling uncovered a regularly spaced pattern of clusters arranged in parallel to the cell growth surfaces. We suggest that this array of MINOS complexes might explain the observed phenomenon of largely horizontally arranged cristae junctions that connect the inner boundary membrane to lamellar cristae. The super-resolution images demonstrate an unexpectedly high level of regularity in the nanoscale distribution of the MINOS complex in human mitochondria, supporting an integrating role of MINOS in the structural organization of the organelle.

Mutations of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) have been found to be linked to Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and/or frontotemporal lobe dementia (FTD). CHCHD2 and CHCHD10 proteins, which are homologous proteins with 54% identity in amino acid sequence, belong to the mitochondrial coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family. A series of studies reveals that these twin proteins form a multimodal complex, producing a variety of pathophysiology by the disease-causing variants of these proteins. In this review, we summarize the present knowledge about the physiological and pathological roles of twin proteins, CHCHD2 and CHCHD10, in neurodegenerative diseases.