bims-mikwok 2021-12-05 papers

Issue of 2021–12–05
eight papers selected by
Avinash N. Mukkala, University of Toronto

Mol Cell Oncol. 2021 ;8(5): 1984162

Mitochondrial homeostasis is maintained in the absence of autophagy.

Autophagy is a central recycling process, and it plays a complex role in cancer. We discovered that when autophagy is blocked, cancer cells compensate by increasing mitochondrial-derived vesicles. However, there are many unanswered questions remaining, particularly in the context of the dual roles of autophagy in cancer.

Keywords: Autophagy; cancer; mitochondria; mitochondrial derived vesicles; mitophagy

DOI: https://doi.org/10.1080/23723556.2021.1984162

Oxid Med Cell Longev. 2021 ;2021 1006636

Mitochondrial Transplantation Attenuates Cerebral Ischemia-Reperfusion Injury: Possible Involvement of Mitochondrial Component Separation.

Qiang Xie, Jun Zeng, Yongtao Zheng, Tianwen Li, Junwei Ren, Kezhu Chen, Quan Zhang, Rong Xie, Feng Xu, Jianhong Zhu.

Background: Mitochondrial dysfunctions play a pivotal role in cerebral ischemia-reperfusion (I/R) injury. Although mitochondrial transplantation has been recently explored for the treatment of cerebral I/R injury, the underlying mechanisms and fate of transplanted mitochondria are still poorly understood.
Methods: Mitochondrial morphology and function were assessed by fluorescent staining, electron microscopy, JC-1, PCR, mitochondrial stress testing, and metabolomics. Therapeutic effects of mitochondria were evaluated by cell viability, reactive oxygen species (ROS), and apoptosis levels in a cellular hypoxia-reoxygenation model. Rat middle cerebral artery occlusion model was applied to assess the mitochondrial therapy in vivo. Transcriptomics was performed to explore the underlying mechanisms. Mitochondrial fate tracking was implemented by a variety of fluorescent labeling methods.
Results: Neuro-2a (N2a) cell-derived mitochondria had higher mitochondrial membrane potential, more active oxidative respiration capacity, and less mitochondrial DNA copy number. Exogenous mitochondrial transplantation increased cellular viability in an oxygen-dependent manner, decreased ROS and apoptosis levels, improved neurobehavioral deficits, and reduced infarct size. Transcriptomic data showed that the differential gene enrichment pathways are associated with metabolism, especially lipid metabolism. Mitochondrial tracking indicated specific parts of the exogenous mitochondria fused with the mitochondria of the host cell, and others were incorporated into lysosomes. This process occurred at the beginning of internalization and its efficiency is related to intercellular connection.
Conclusions: Mitochondrial transplantation may attenuate cerebral I/R injury. The mechanism may be related to mitochondrial component separation, altering cellular metabolism, reducing ROS, and apoptosis in an oxygen-dependent manner. The way of isolated mitochondrial transfer into the cell may be related to intercellular connection.

DOI: https://doi.org/10.1155/2021/1006636

J Cell Sci. 2021 Dec 02. pii: jcs.259254. [Epub ahead of print]

Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.

Imadeddin Hijazi, Emily Wang, Michelle Orozco, Sarah Pelton, Amy Chang.

Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.

Keywords: Endoplasmic reticulum; Mitochondria; Stress survival

DOI: https://doi.org/10.1242/jcs.259254

J Physiol. 2021 Nov 27.

Metabolic design in a mammalian model of extreme metabolism, the North American least shrew (Cryptotis parva).

Dillon J Chung, Grey P Madison, Angel M Aponte, Komudi Singh, Yuesheng Li, Mehdi Pirooznia, Christopher K E Bleck, Nissar A Darmani, Robert S Balaban.

KEY POINTS: Least shrews were studied to explore the relationship between metabolic function, mitochondrial morphology and protein content in different tissues. Liver and kidney mitochondrial content and enzymatic activity approaches the heart indicating similar metabolic demand among tissues that contribute to basal and maximum metabolism. This allows examination of mitochondrial structure and composition in tissues with similar maximum metabolic demands. Mitochondrial networks only occur in striated muscle. In contrast, the liver and kidney maintain individual mitochondria with limited reticulation. Muscle mitochondrial reticulation is the result of dense ATPase activity and cell-spanning myofibrils which require networking for adequate metabolic support. In contrast, liver and kidney ATPase activity is localized to the endoplasmic reticulum and basolateral membrane respectively, generating a locally balanced energy conversion and utilization Mitochondrial morphology is not driven by maximum metabolic demand, but by the cytosolic distribution of energy utilizing systems set by the functions of the tissue.
ABSTRACT: Mitochondrial adaptations are fundamental to differentiated function and energetic homeostasis in mammalian cells. But the mechanisms that underlie these relationships remain poorly understood. Here, we investigated organ-specific mitochondrial morphology, connectivity and protein composition in a model of extreme mammalian metabolism, the Least shrew (Cryptotis parva). This was achieved through a combination of high-resolution 3D focused-ion-beam EM imaging and tandem-mass-tag MS proteomics. We demonstrate that liver and kidney mitochondrial content are equivalent to the heart permitting assessment of mitochondrial adaptations in different organs with similar metabolic demand. Muscle mitochondrial networks (cardiac and skeletal) are extensive, with a high incidence of nanotunnels - which collectively support the metabolism of large muscle cells. Mitochondrial networks were not detected in the liver and kidney as individual mitochondria are localized with sites of ATP consumption. This configuration is not observed in striated muscle, likely due to a homogenous ATPase distribution and the structural requirements of contraction. These results demonstrate distinct, fundamental mitochondrial structural adaptations for similar metabolic demand that are dependent on the topology of energy utilization process in a mammalian model of extreme metabolism. Abstract figure. This study investigates the role of mitochondrial morphology and protein composition in setting the extreme metabolic rates of one of the smallest extant mammals - the North American least shrew (Cryptotis parva). To do this, mitochondrial characteristics from liver, kidney, skeletal muscle and heart tissues were compared as these tissues are major contributors to basal and maximum metabolic states. Liver and kidney mitochondrial volume density and protein content approach levels observed in the heart - indicating that these former tissues are major contributors to the high basal metabolic rates of small mammals. Despite this high mitochondrial content, the liver and kidney do not exhibit mitochondrial networking - structures that are proposed to conduct mitochondrial proton motive force at the scale of the cell. Shrew skeletal muscle and cardiac mitochondrial network organization is consistent with networks observed in larger mammals while also exhibiting increased connectivity at the nm-scale. Instead of forming networks, kidney and liver mitochondria are directly associated with sites of ATP utilization. These results identify conditions that dictate the formation of mitochondrial networks and processes that drive mammalian allometric scaling of metabolic rates. This article is protected by copyright. All rights reserved.

Keywords:

DOI: https://doi.org/10.1113/JP282153

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

Cell Death Differ. 2021 Nov 27.

USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1.

Yuluo Rong, Jin Fan, Chengyue Ji, Zhuanghui Wang, Xuhui Ge, Jiaxing Wang, Wu Ye, Guoyong Yin, Weihua Cai, Wei Liu.

Spinal cord ischemia-reperfusion injury (SCIRI) is a serious trauma that can lead to loss of sensory and motor function. Ferroptosis is a new form of regulatory cell death characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis has been studied in various diseases; however, the exact function and molecular mechanism of ferroptosis in SCIRI remain unknown. In this study, we demonstrated that ferroptosis is involved in the pathological mechanism of SCIRI. Inhibition of ferroptosis could promote the recovery of motor function in mice after SCIRI. In addition, we found that ubiquitin-specific protease 11 (USP11) was significantly upregulated in neuronal cells after hypoxia-reoxygenation and in the spinal cord in mice with I/R injury. Knockdown of USP11 in vitro and KO of USP11 in vivo (USP11-/Y) significantly decreased neuronal cell ferroptosis. In mice, this promotes functional recovery after SCIRI. In contrast, in vitro, USP11 overexpression leads to classic ferroptosis events. Overexpression of USP11 in mice resulted in increased ferroptosis and poor functional recovery after SCIRI. Interestingly, upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux, a potential mechanism through which USP11 may enhance ferroptosis. The decreased autophagy markedly weakened the ferroptosis mediated by USP11 and autophagy induction had a synergistic effect with USP11. Importantly, USP11 promotes autophagy activation by stabilizing Beclin 1, thereby leading to ferroptosis. In conclusion, this study shows that ferroptosis is closely associated with SCIRI, and that USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of SCIRI.

DOI: https://doi.org/10.1038/s41418-021-00907-8

Commun Biol. 2021 Dec 02. 4(1): 1350

ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.

Adrián Cortés Sanchón, Harshitha Santhosh Kumar, Matilde Mantovani, Ivan Osinnii, José María Mateos, Andres Kaech, Dimitri Shcherbakov, Rashid Akbergenov, Erik C Böttger.

Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Here we show by cell fractionation and microscopy studies that misfolded proteins formed in the endoplasmic reticulum can become associated with and partly transported into mitochondria, resulting in impaired mitochondrial function. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp1 and Vms1, abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). We testify to the relevance of this pathway by using mutant α-1-antitrypsin as an example of a human disease-related misfolded ER protein, and we hypothesize that ERAMS plays a role in pathological features such as mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s42003-021-02873-w

ANZ J Surg. 2021 Dec 02.

The hepatoprotective effect from ischemia-reperfusion injury of remote ischemic preconditioning in the liver related surgery: a meta-analysis.

Jinli Wu, Chao Yu, Xianggang Zeng, Chengyi Sun.

BACKGROUND: This study aimed to assess the hepatoprotective effect of remote ischemic preconditioning (RIPC) in the liver related surgery.
METHODS: Published articles in PubMed, Embase and Cochrane clinical trial databases were searched from the inception to May 2021. Randomized control trials (RCTs) comparing the RIPC with control or other conditionings were included for analysis. The postoperative liver synthetic function was used as the primary outcome.
RESULTS: A total of six RCTs were included the present meta-analysis. There were 216 patients underwent RIPC and 212 patients in the control group. The RIPC group had a significantly lower level of postoperative alanine transaminase and aspartate transaminase (p<0.001). The postoperative bilirubin level was also significant lower in the RIPC group than the control group (MD = -9.0, 95%CI, -13.94 to -4.03; p<0.001). ICG clearance was reduced in controls versus RIPC (p<0.001). There was no significant difference between the RIPC and control group in terms of the complication rate.
CONCLUSION: The RIPC was evaluated to have a strong hepatoprotective effect from ischemia-reperfusion injury in the liver related surgery.

Keywords: liver resection; meta-analysis; randomized control trials; remote ischemic preconditioning

DOI: https://doi.org/10.1111/ans.17236