Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.

The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far.

Structural mechanism of mitochondrial membrane remodelling by human OPA1.

Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear.

Central role of Tim17 in mitochondrial presequence protein translocation.

The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria. About 60% of more than 1,000 different mitochondrial proteins are synthesized with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices. TIM23 sorts the presequence proteins into the inner membrane or matrix.

Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.

The presequence translocase (TIM23 complex) imports precursor proteins into the mitochondrial inner membrane and matrix. The presequence translocase-associated motor (PAM) provides a driving force for transport into the matrix. The J-protein Pam18 stimulates the ATPase activity of the mitochondrial Hsp70 (mtHsp70).

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

Invaginations of the mitochondrial inner membrane, termed cristae, are hubs for oxidative phosphorylation. The mitochondrial contact site and cristae organizing system (MICOS) and the dimeric FF-ATP synthase play important roles in controlling cristae architecture. A fraction of the MICOS core subunit Mic10 is found in association with the ATP synthase, yet it is unknown whether this interaction is of relevance for mitochondrial or cellular functions.

Loss of Mitochondrial Ca Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

Background: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise, and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS).

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer's Disease Model.

Alzheimer's disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and lipid-homeostasis exists, little is known about potential alterations in the lipid composition of mitochondria.

Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria.

Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown.

Transmembrane Coordination of Preprotein Recognition and Motor Coupling by the Mitochondrial Presequence Receptor Tim50.

Mitochondrial preproteins contain amino-terminal presequences directing them to the presequence translocase of the mitochondrial inner membrane (TIM23 complex). Depending on additional downstream import signals, TIM23 either inserts preproteins into the inner membrane or translocates them into the matrix. Matrix import requires the coupling of the presequence translocase-associated motor (PAM) to TIM23.

The Mgr2 subunit of the TIM23 complex regulates membrane insertion of marginal stop-transfer signals in the mitochondrial inner membrane.

The TIM23 complex mediates membrane insertion of presequence-containing mitochondrial proteins via a stop-transfer mechanism. Stop-transfer signals consist of hydrophobic transmembrane segments and flanking charges. Mgr2 functions as a lateral gatekeeper of the TIM23 complex.

Structure and assembly of the mitochondrial membrane remodelling GTPase Mgm1.

Balanced fusion and fission are key for the proper function and physiology of mitochondria. Remodelling of the mitochondrial inner membrane is mediated by the dynamin-like protein mitochondrial genome maintenance 1 (Mgm1) in fungi or the related protein optic atrophy 1 (OPA1) in animals. Mgm1 is required for the preservation of mitochondrial DNA in yeast, whereas mutations in the OPA1 gene in humans are a common cause of autosomal dominant optic atrophy-a genetic disorder that affects the optic nerve.

Publisher Correction: Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme.

In the version of this article originally published, parts of Figure 5 were misaligned because of a shift during production. In a, one data point was outside of the graph border. In b, axes lines were not connected, and graph lines did not reach the data points.

Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme.

The cytosolic accumulation of mitochondrial precursors is hazardous to cellular fitness and is associated with a number of diseases. However, it is not observed under physiological conditions. Individual mechanisms that allow cells to avoid cytosolic accumulation of mitochondrial precursors have recently been discovered, but their interplay and regulation remain elusive.

Vps39 Interacts with Tom40 to Establish One of Two Functionally Distinct Vacuole-Mitochondria Contact Sites.

The extensive subcellular network of membrane contact sites plays central roles in organelle biogenesis and communication, yet the precise contributions of the involved machineries remain largely enigmatic. The yeast vacuole forms a membrane contact site with mitochondria, called vacuolar and mitochondrial patch (vCLAMP). Formation of vCLAMPs involves the vacuolar Rab GTPase Ypt7 and the Ypt7-interacting Vps39 subunit of the HOPS tethering complex.

Assembly of the Mitochondrial Cristae Organizer Mic10 Is Regulated by Mic26-Mic27 Antagonism and Cardiolipin.

The multi-subunit mitochondrial contact site and cristae organizing system (MICOS) is a conserved protein complex of the inner mitochondrial membrane that is essential for maintenance of cristae architecture. The core subunit Mic10 forms large oligomers that build a scaffold and induce membrane curvature. The regulation of Mic10 oligomerization is poorly understood.

No Longer Hidden Secrets of Proton Pumping: The Resolution Revolution Enlightens V-ATPases.

In this issue of Molecular Cell, Roh et al. (2018) present a high-resolution cryo-EM structure of the nanodisc-reconstituted yeast V proton channel that provides important new insights into subunit arrangements and the proton translocation pathway in V-type ATPases.

Integrative functions of the mitochondrial contact site and cristae organizing system.

Mitochondria are complex double-membrane-bound organelles of eukaryotic cells that function as energy-converting powerhouses, metabolic factories and signaling centers. The outer membrane controls the exchange of material and information with other cellular compartments. The inner membrane provides an extended, highly folded surface for selective transport and energy-coupling reactions.

The Yin & Yang of Mitochondrial Architecture - Interplay of MICOS and FF-ATP synthase in cristae formation.

Oxidative phosphorylation takes place at specialized compartments of the inner mitochondrial membrane, the cristae. The elaborate ultrastructure of cristae membranes enables efficient chemi-osmotic coupling of respiratory chain and FF-ATP synthase. Dynamic membrane remodeling allows mitochondria to adapt to changing physiological requirements.

Parkin promotes proteasomal degradation of misregulated BAX.

The pro-apoptotic BCL-2 protein BAX commits human cells to apoptosis by permeabilizing the outer mitochondrial membrane. BAX activation has been suggested to require the separation of helix α5 from α6 - the 'latch' from the 'core' domain - among other conformational changes. Here, we show that conformational changes in this region impair BAX translocation to the mitochondria and retrotranslocation back into the cytosol, and therefore BAX inhibition, but not activation.

Definition of a High-Confidence Mitochondrial Proteome at Quantitative Scale.

Mitochondria perform central functions in cellular bioenergetics, metabolism, and signaling, and their dysfunction has been linked to numerous diseases. The available studies cover only part of the mitochondrial proteome, and a separation of core mitochondrial proteins from associated fractions has not been achieved. We developed an integrative experimental approach to define the proteome of yeast mitochondria.

Regulated membrane remodeling by Mic60 controls formation of mitochondrial crista junctions.

The mitochondrial contact site and cristae organizing system (MICOS) is crucial for the formation of crista junctions and mitochondrial inner membrane architecture. MICOS contains two core components. Mic10 shows membrane-bending activity, whereas Mic60 (mitofilin) forms contact sites between inner and outer membranes.

Mitochondrial contact site and cristae organizing system: A central player in membrane shaping and crosstalk.

Mitochondria are multifunctional metabolic factories and integrative signaling organelles of eukaryotic cells. The structural basis for their numerous functions is a complex and dynamic double-membrane architecture. The outer membrane connects mitochondria to the cytosol and other organelles.