bims-mecmid 2021-12-05 papers

Open Biol. 2021 Dec;11(12): 210238

Pathways shaping the mitochondrial inner membrane.

Mitochondria are complex organelles with two membranes. Their architecture is determined by characteristic folds of the inner membrane, termed cristae. Recent studies in yeast and other organisms led to the identification of four major pathways that cooperate to shape cristae membranes. These include dimer formation of the mitochondrial ATP synthase, assembly of the mitochondrial contact site and cristae organizing system (MICOS), inner membrane remodelling by a dynamin-related GTPase (Mgm1/OPA1), and modulation of the mitochondrial lipid composition. In this review, we describe the function of the evolutionarily conserved machineries involved in mitochondrial cristae biogenesis with a focus on yeast and present current models to explain how their coordinated activities establish mitochondrial membrane architecture.

Keywords: ATP synthase; MICOS; Mgm1; Saccharomyces cerevisiae; cristae; mitochondrial lipids

DOI: https://doi.org/10.1098/rsob.210238

Signal Transduct Target Ther. 2021 Dec 01. 6(1): 401

Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis.

Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

DOI: https://doi.org/10.1038/s41392-021-00790-2

Mol Cell. 2021 Nov 19. pii: S1097-2765(21)00954-0. [Epub ahead of print]

Global mitochondrial protein import proteomics reveal distinct regulation by translation and translocation machinery.

Jasmin Adriana Schäfer, Süleyman Bozkurt, Jonas Benjamin Michaelis, Kevin Klann, Christian Münch.

Most mitochondrial proteins are translated in the cytosol and imported into mitochondria. Mutations in the mitochondrial protein import machinery cause human pathologies. However, a lack of suitable tools to measure protein uptake across the mitochondrial proteome has prevented the identification of specific proteins affected by import perturbation. Here, we introduce mePRODmt, a pulsed-SILAC based proteomics approach that includes a booster signal to increase the sensitivity for mitochondrial proteins selectively, enabling global dynamic analysis of endogenous mitochondrial protein uptake in cells. We applied mePRODmt to determine protein uptake kinetics and examined how inhibitors of mitochondrial import machineries affect protein uptake. Monitoring changes in translation and uptake upon mitochondrial membrane depolarization revealed that protein uptake was extensively modulated by the import and translation machineries via activation of the integrated stress response. Strikingly, uptake changes were not uniform, with subsets of proteins being unaffected or decreased due to changes in translation or import capacity.

Keywords: SILAC; TMT; disease; integrated stress response; mitochondria; protein translocation; proteomics; proteostasis; respiratory chain complexes; translation

DOI: https://doi.org/10.1016/j.molcel.2021.11.004

Clin Genet. 2021 Nov 29.

Mitochondrial Developmental encephalopathy with bilateral optic neuropathy related to homozygous variants in IMMT gene.

Ana Victoria Marco-Hernández, Miguel Tomás-Vila, Alejandro Montoya-Filardi, Honorio Barranco-González, Juan Jesus Vilchez Padilla, Inmaculada Azorín, Patricia Smeyers Dura, Sandra Monfort-Membrado, Inmaculada Pitarch-Castellano, Francisco Martínez-Castellano.

IMMT gene codes for mitofilin, a mitochondrial inner membrane protein that regulates the morphology of mitochondrial cristae. The phenotype associated with mutations in this gene has not been yet established, but functional studies carried out show that its loss causes a mitochondrial alteration, both in the morphology of the mitochondrial crests and in their function. We present two cousins from an extended highly consanguineous family with developmental encephalopathy, hypotonia, nystagmus due to optic neuropathy. The likely pathogenic homozygous c.895A > G (p.Lys299Glu) variant in the IMMT gene co-segregates with the disease and associates altered mitochondrial cristae observed by electron microscopy.

Keywords: IMMT gene; developmental encephalopathy; mitochondrial disorder; mitofilin complexes; nystagmus; optic neuropathy

DOI: https://doi.org/10.1111/cge.14093

Adv Biol (Weinh). 2021 Dec 03. e2101020

Remodeling of Membrane Shape and Topology by Curvature Elasticity and Membrane Tension.

Reinhard Lipowsky.

Cellular membranes exhibit a fascinating variety of different morphologies, which are continuously remodeled by transformations of membrane shape and topology. This remodeling is essential for important biological processes (cell division, intracellular vesicle trafficking, endocytosis) and can be elucidated in a systematic and quantitative manner using synthetic membrane systems. Here, recent insights obtained from such synthetic systems are reviewed, integrating experimental observations and molecular dynamics simulations with the theory of membrane elasticity. The study starts from the polymorphism of biomembranes as observed for giant vesicles by optical microscopy and small nanovesicles in simulations. This polymorphism reflects the unusual elasticity of fluid membranes and includes the formation of membrane necks or fluid 'worm holes'. The proliferation of membrane necks generates stable multi-spherical shapes, which can form tubules and tubular junctions. Membrane necks are also essential for the remodeling of membrane topology via membrane fission and fusion. Neck fission can be induced by fine-tuning of membrane curvature, which leads to the controlled division of giant vesicles, and by adhesion-induced membrane tension as observed for small nanovesicles. Challenges for future research include the interplay of curvature elasticity and membrane tension during membrane fusion and the localization of fission and fusion processes within intramembrane domains.

Keywords: fission; fusion; membrane elasticity; membranes; synthetic biosystems; vesicles

DOI: https://doi.org/10.1002/adbi.202101020

Exp Gerontol. 2021 Nov 30. pii: S0531-5565(21)00430-7. [Epub ahead of print] 111648

Effects of high-intensity interval training on mitochondrial supercomplex assembly and biogenesis, mitophagy, and the AMP-activated protein kinase pathway in the soleus muscle of aged female rats.

Chong Han, Peng Lu, Shi-Zhan Yan.

PURPOSE: Exercise helps improve mitochondrial function to combat sarcopenia. Certain parts of the mitochondrial respiratory chain complex can form a higher-order structure called "supercomplex" to reduce the production of reactive oxygen species and improve muscle mass. The effect of exercise on the assembly of the mitochondrial supercomplex is still unclear. The aim of this study was to investigate the effects of long-term high-intensity interval training (HIIT) on mitochondrial biogenesis, mitophagy, and mitochondrial supercomplexes (mitoSCs) assembly in aging soleus muscle.
METHODS: Female Sprague-Dawley rats (n = 36) were randomly divided into four groups: young sedentary (Y-SED, 8 months old, n = 12), old sedentary (O-SED, 26 months old, n = 12), moderate-intensity continuous training (MICT, from 18 to 26 months old, n = 12), and HIIT (from 18 to 26 months old, n = 12). Rats in the MICT and HIIT groups were subjected to an 8-month training program. Real-time fluorescent quantitative polymerase chain reaction was used to measure the expression of the antioxidative factors, inflammatory factors, and mitochondrial fusion- and division-related genes. Western blotting was used to detect the expression of mitochondrial biogenesis and mitophagy markers and AMP-activated protein kinase (AMPK) pathway proteins. Enzyme-linked immunosorbent assays were used to determine serum irisin contents. Blue native polyacrylamide gel electrophoresis was used to assess the formation of mitochondrial supercomplexes.
RESULTS: Compared with the Y-SED group, the soleus muscle and mitochondria in the O-SED group showed reduced expression of mitophagy- and mitochondrial biogenesis-related proteins. In the HIIT group, the expression of autophagy-related proteins in the soleus muscle and mitochondria was significantly increased compared with that in the MICT group. Serum irisin and mitochondrial fusion protein levels significantly decreased with age. Superoxide dismutase 2 protein levels and AMPK pathway protein expression were significantly increased in the HIIT group compared with those in the other groups. Additionally, the expression levels of mitoSCs and the mRNA levels of interleukin-15 and optical atrophy 1 increased in the HIIT group compared with that in the MICT group.
CONCLUSION: Compared with MICT, HIIT activated the AMPK pathway to upregulate mitochondrial biogenesis- and mitophagy-related proteins, and promote the assembly and formation of mitoSCs to improve the mitochondrial function of aging soleus muscles.

Keywords: AMPK pathway; High-intensity interval training, aging; Mitochondrial supercomplex; Mitophagy

DOI: https://doi.org/10.1016/j.exger.2021.111648

DNA Cell Biol. 2021 Dec 01.

Quality Control Mechanisms of Mitochondria: Another Important Target for Treatment of Peripheral Neuropathy.

Te Zhang, Jiannan Li, Guoqing Zhao.

Mitochondria provide energy for various cellular activities and are involved in the regulating of several physiological and pathological processes. Mitochondria constitute a dynamic network regulated by numerous quality control mechanisms; for example, division is necessary for mitochondria to develop, and fusion dilutes toxins produced by the mitochondria. Mitophagy removes damaged mitochondria. The etiologies of peripheral neuropathy include congenital and acquired diseases, and the pathogenesis varies; however, oxidative stress caused by mitochondrial damage is the accepted pathogenesis of peripheral neuropathy. Regulation and control of mitochondrial quality might point the way toward potential treatments for peripheral neuropathy. This article will review mitochondrial quality control mechanisms, their involvement in peripheral nerve diseases, and their potential therapeutic role.

Keywords: mitochondria; mitochondrial dynamics; mitophagy; pain; peripheral neuropathy

DOI: https://doi.org/10.1089/dna.2021.0529