Mechanical instability generated by Myosin 19 contributes to mitochondria cristae architecture and OXPHOS.

The folded mitochondria inner membrane-cristae is the structural foundation for oxidative phosphorylation (OXPHOS) and energy production. By mechanically simulating mitochondria morphogenesis, we speculate that efficient sculpting of the cristae is organelle non-autonomous. It has long been inferred that folding requires buckling in living systems. However, the tethering force for cristae formation and regulation has not been identified. Combining electron tomography, proteomics strategies, super resolution live cell imaging and mathematical modeling, we reveal that the mitochondria localized actin motor-myosin 19 (Myo19) is critical for maintaining cristae structure, by associating with the SAM-MICOS super complex. We discover that depletion of Myo19 or disruption of its motor activity leads to altered mitochondria membrane potential and decreased OXPHOS. We propose that Myo19 may act as a mechanical tether for effective ridging of the mitochondria cristae, thus sustaining the energy homeostasis essential for various cellular functions.

The Golgi microtubules regulate single cell durotaxis.

Current understandings on cell motility and directionality rely heavily on accumulated investigations of the adhesion-actin cytoskeleton-actomyosin contractility cycles, while microtubules have been understudied in this context. Durotaxis, the ability of cells to migrate up gradients of substrate stiffness, plays a critical part in development and disease. Here, we identify the pivotal role of Golgi microtubules in durotactic migration of single cells. Using high-throughput analysis of microtubule plus ends/focal adhesion interactions, we uncover that these non-centrosomal microtubules actively impart leading edge focal adhesion (FA) dynamics. Furthermore, we designed a new system where islands of higher stiffness were patterned within RGD peptide coated polyacrylamide gels. We revealed that the positioning of the Golgi apparatus is responsive to external mechanical cues and that the Golgi-nucleus axis aligns with the stiffness gradient in durotaxis. Together, our work unveils the cytoskeletal underpinning for single cell durotaxis. We propose a model in which the Golgi-nucleus axis serves both as a compass and as a steering wheel for durotactic migration, dictating cell directionality through the interaction between non-centrosomal microtubules and the FA dynamics.

Identification of Serum Biomarker in Acute Aortic Dissection by Global and Targeted Metabolomics.

BACKGROUND: Acute aortic dissection (AAD) is the most devastating aortic pathology, and the incidence is increasing worldwide. However, the occurrence and development of AAD are unpredictable. A thorough understanding of the serum metabolic landscape through metabolomic analysis may help identify new biomarkers for AAD and offers new insights into its prevention and evaluation. METHODS: Nineteen patients with Stanford type A aortic dissection and 20 healthy individuals were enrolled in this study. We use global and targeted mass spectrometry-based metabolomics to investigate the serum metabolomics profiles, and the data were analyzed by principal component analysis and orthogonal partial least squares discriminant analysis. RESULTS: Initial untargeted metabolomics analysis revealed significant changes of lipids and polar metabolites in patients with AAD. Alterations of the phosphatidylcholine metabolic pathway were further observed by targeted metabolomics. Trimethylamine N-oxide (TMAO) levels were obviously increased in patients with AAD compared with controls (P < 0.005), whereas the levels of carnitine (P < 0.005), choline, and betaine (P < 0.05) were decreased. Furthermore, TMAO levels were associated with disease severity in AAD and correlated positively with C-reactive protein levels (r = 0.537, P = 0.018), IL-6 levels (r = 0.546, P = 0.016), D-dimer levels (r = 0.694, P = 0.001), and maximum aortic diameter on admission (r = 0.748, P = 0.002). CONCLUSIONS: Patients with AAD showed a predominant and consistent change of metabolites levels, especially the compounds in the phosphatidylcholine metabolic pathway. TMAO could potentially serve as a biomarker for the auxiliary diagnosis and evaluation of AAD.

Cirrhotic stiffness affects the migration of hepatocellular carcinoma cells and induces sorafenib resistance through YAP.

A majority of hepatocellular carcinomas (HCCs) combine with liver cirrhosis. The cirrhotic liver has been implicated in interfering with the effects of HCC-targeted drugs, including sorafenib. Alterations in the tumor microenvironment of the cirrhotic liver include both biochemical and biomechanical factors. In this study, we induced sorafenib resistance in HCC cells. We observed changes in cell morphology, cytoskeletal architecture, and cellular stiffness in these sorafenib-resistant cells, resembling those adapted to stiffer substrates. To examine the contribution of mechanical factors in HCC cell growth and drug resistance, we used an in vitro cell culture system with adjustable stiffness mimicking the normal or cirrhotic liver tissues. We identified that mechanical adaptation conferred HCC cells with increased motility and sorafenib resistance. We further reported the mechanism underlying the involvement of the transcription coactivator YAP. Our results underline the important role of mechanical factors in the interaction between tumor cells and their microenvironment.