bims-mikwok 2023-01-22 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒01‒22
eight papers selected by
Avinash N. Mukkala, University of Toronto

Lineage-Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells.
Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
Special Issue: Advancing mitochondria as a therapeutic agenta.
Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.
Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures.
Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis.
Key Hepatoprotective Roles of Mitochondria in Liver Regeneration.
CoQ10 alleviates hepatic ischemia reperfusion injury via inhibiting NLRP3 activity and promoting Tregs infiltration.

Adv Biol (Weinh). 2023 Jan 18. e2200246

Lineage-Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells.

Fausto Capelluto, Hannah Alberico, Paula Ledo-Hopgood, Jonathan L Tilly, Dori C Woods.

  In addition to critical roles in bioenergetics, mitochondria are key contributors to the regulation of many other functions in cells, ranging from steroidogenesis to apoptosis. Numerous studies further demonstrate that cell type-specific differences exist in mitochondria, with cells of a given lineage tailoring their endogenous mitochondrial population to suit specific functional needs. These findings, coupled with studies of the therapeutic potential of mitochondrial transplantation, provide a strong impetus to better understand how mitochondria can influence cell function or fate. Here an inducible mitochondrial depletion modelis used to study how cells lacking endogenous mitochondria respond, on a global protein expression level, to transplantation with lineage-mismatched (LM) mitochondria. It is shown that LM mitochondrial transplantation does not alter the proteomic profile in nonmitochondria-depleted recipient cells; however, enforced depletion of endogenous mitochondria results in dramatic changes in the proteomic landscape, which returns to the predepletion state following internalization of LM mitochondria. These data, derived from a cell system that can be rendered free of influence by endogenous mitochondria, indicate that transplantation of mitochondria-even from a source that differs significantly from the recipient cell population, effectively restores a normal proteomic landscape to cells lacking their own mitochondria.

Keywords:  Parkin; mitochondria; mitochondrial depletion; mitochondrial transplantation; proteomics

DOI:  https://doi.org/10.1002/adbi.202200246
Nat Cell Biol. 2023 Jan 19.

Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.

Soni Deshwal, Mashun Onishi, Takashi Tatsuta, Tim Bartsch, Eileen Cors, Katharina Ried, Kathrin Lemke, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

DOI: https://doi.org/10.1038/s41556-022-01071-y
Mitochondrion. 2023 Jan 16. pii: S1567-7249(23)00003-X. [Epub ahead of print]

Special Issue: Advancing mitochondria as a therapeutic agenta.

Andrés Caicedo, Keshav K Singh.

This article intends to provide an update of the needs in the field working in the artificial mitochondrial transfer/transplant (AMT/T), and an overview of the article updates from the special issue "Advances of Mitochondria as a therapeutic agent". In the last 4 decades, scientists developed innovative therapeutic applications based on the AMT/T, inspired by the natural transfer of mitochondria between cells to repair cellular damage or treat diseases. The clinical application of AMT has become the priority for the field involving the replacement or augmentation of healthy mitochondria in the harmed tissue, especially in the treatment of organ ischemia-reperfusion injury. However, we remark in our article that key questions remain to be answer such which one is the best isolation protocol, tissue or cell source for isolation, and others of great importance to move the field forward.

DOI: https://doi.org/10.1016/j.mito.2023.01.003
J Biol Chem. 2023 Jan 12. pii: S0021-9258(23)00036-4. [Epub ahead of print] 102904

Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.

Eloisa A Vilas-Boas, João Victor Cabral-Costa, Vitor M Ramos, Camille C Caldeira da Silva, Alicia J Kowaltowski.

  Calcium (Ca2+) is a key regulator in diverse intracellular signaling pathways, and has long been implicated in metabolic control and mitochondrial function. Mitochondria can actively take up large amounts of Ca2+, thereby acting as important intracellular Ca2+ buffers and affecting cytosolic Ca2+ transients. Excessive mitochondrial matrix Ca2+ is known to be deleterious due to opening of the mitochondrial permeability transition pore (mPTP) and consequent membrane potential dissipation, leading to mitochondrial swelling, rupture, and cell death. Moderate Ca2+ within the organelle, on the other hand, can directly or indirectly activate mitochondrial matrix enzymes, possibly impacting on ATP production. Here, we aimed to determine in a quantitative manner if extra or intramitochondrial Ca2+ modulate oxidative phosphorylation in mouse liver mitochondria and intact hepatocyte cell lines. To do so, we monitored the effects of more modest versus supra-physiological increases in cytosolic and mitochondrial Ca2+ on oxygen consumption rates. Isolated mitochondria present increased respiratory control ratios (a measure of oxidative phosphorylation efficiency) when incubated with low (2.4 ± 0.6 μM) and medium (22.0 ± 2.4 μM) Ca2+ concentrations in the presence of complex I-linked substrates pyruvate plus malate and α-ketoglutarate, respectively, but not complex II-linked succinate. In intact cells, both low and high cytosolic Ca2+ led to decreased respiratory rates, while ideal rates were present under physiological conditions. High Ca2+ decreased mitochondrial respiration in a substrate-dependent manner, mediated by mPTP. Overall, our results uncover a Goldilocks effect of Ca2+ on liver mitochondria, with specific "just right" concentrations that activate oxidative phosphorylation.

Keywords:  calcium transport; electron transfer chain; metabolic flux; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2023.102904
J Control Release. 2023 Jan 18. pii: S0168-3659(23)00026-3. [Epub ahead of print]354 368-393

Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures.

Kandarp M Dave, Donna B Stolz, Venugopal R Venna, Victoria A Quaicoe, Michael E Maniskas, Michael John Reynolds, Riyan Babidhan, Duncan X Dobbins, Maura N Farinelli, Abigail Sullivan, Tarun N Bhatia, Hannah Yankello, Rohan Reddy, Younsoo Bae, Rehana K Leak, Sruti S Shiva, Louise D McCullough, Devika S Manickam.

  Ischemic stroke causes brain endothelial cell (BEC) death and damages tight junction integrity of the blood-brain barrier (BBB). We harnessed the innate mitochondrial load of BEC-derived extracellular vesicles (EVs) and utilized mixtures of EV/exogenous 27 kDa heat shock protein (HSP27) as a one-two punch strategy to increase BEC survival (via EV mitochondria) and preserve their tight junction integrity (via HSP27 effects). We demonstrated that the medium-to-large (m/lEV) but not small EVs (sEV) transferred their mitochondrial load, that subsequently colocalized with the mitochondrial network of the recipient primary human BECs. Recipient BECs treated with m/lEVs showed increased relative ATP levels and mitochondrial function. To determine if the m/lEV-meditated increase in recipient BEC ATP levels was associated with m/lEV mitochondria, we isolated m/lEVs from donor BECs pre-treated with oligomycin A (OGM, mitochondria electron transport complex V inhibitor), referred to as OGM-m/lEVs. BECs treated with naïve m/lEVs showed a significant increase in ATP levels compared to untreated OGD cells, OGM-m/lEVs treated BECs showed a loss of ATP levels suggesting that the m/lEV-mediated increase in ATP levels is likely a function of their innate mitochondrial load. In contrast, sEV-mediated ATP increases were not affected by inhibition of mitochondrial function in the donor BECs. Intravenously administered m/lEVs showed a reduction in brain infarct sizes compared to vehicle-injected mice in a mouse middle cerebral artery occlusion model of ischemic stroke. We formulated binary mixtures of human recombinant HSP27 protein with EVs: EV/HSP27 and ternary mixtures of HSP27 and EVs with a cationic polymer, poly (ethylene glycol)-b-poly (diethyltriamine): (PEG-DET/HSP27)/EV. (PEG-DET/HSP27)/EV and EV/HSP27 mixtures decreased the paracellular permeability of small and large molecular mass fluorescent tracers in oxygen glucose-deprived primary human BECs. This one-two punch approach to increase BEC metabolic function and tight junction integrity may be a promising strategy for BBB protection and prevention of long-term neurological dysfunction post-ischemic stroke.

Keywords:  BBB protection; Extracellular vesicles; Heat shock protein; Ischemic stroke; Mitochondria; Paracellular permeability

DOI:  https://doi.org/10.1016/j.jconrel.2023.01.025
Exp Mol Med. 2023 Jan 19.

Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis.

Ne N Wu, Lifeng Wang, Lu Wang, Xihui Xu, Gary D Lopaschuk, Yingmei Zhang, Jun Ren.

Mitochondrial DNA (mtDNA) released through protein oligomers, such as voltage-dependent anion channel 1 (VDAC1), triggers innate immune activation and thus contributes to liver fibrosis. Here, we investigated the role of Parkin, an important regulator of mitochondria, and its regulation of VDAC1-mediated mtDNA release in liver fibrosis. The circulating mitochondrial DNA (mtDNA) and protein levels of liver Parkin and VDAC1 were upregulated in patients with liver fibrosis. A 4-week CCl4 challenge induced release of mtDNA, activation of STING signaling, a decline in autophagy, and apoptosis in mouse livers, and the knockout of Parkin aggravated these effects. In addition, Parkin reduced mtDNA release and prevented VDAC1 oligomerization in a manner dependent on its E3 activity in hepatocytes. We found that site-specific ubiquitination of VDAC1 at lysine 53 by Parkin interrupted VDAC1 oligomerization and prevented mtDNA release into the cytoplasm under stress. The ubiquitination-defective VDAC1 K53R mutant predominantly formed oligomers that resisted suppression by Parkin. Hepatocytes expressing VDAC1 K53R exhibited mtDNA release and thus activated the STING signaling pathway in hepatic stellate cells, and this effect could not be abolished by Parkin. We propose that the ubiquitination of VDAC1 at a specific site by Parkin confers protection against liver fibrosis by interrupting VDAC1 oligomerization and mtDNA release.

DOI: https://doi.org/10.1038/s12276-022-00923-9
Am J Physiol Gastrointest Liver Physiol. 2023 Jan 17.

Key Hepatoprotective Roles of Mitochondria in Liver Regeneration.

Gene G Lamanilao, Murat Dogan, Prisha S Patel, Shafquat Azim, Disha S Patel, Syamal K Bhattacharya, James D Eason, Canan Kuscu, Cem Kuscu, Amandeep Bajwa.

  Treatment of advanced liver disease using surgical modalities is possible due to the liver's innate ability to regenerate following resection. Several key cellular events in the regenerative process converge at the mitochondria, implicating its crucial roles in liver regeneration. Mitochondria enable the regenerating liver to meet immense metabolic demands by coordinating energy production to drive cellular proliferative processes and vital homeostatic functions. Mitochondria are also involved in terminating the regenerative process by mediating apoptosis. Studies have shown that attenuation of mitochondrial activity results in delayed liver regeneration, and liver failure following resection is associated with mitochondrial dysfunction. Emerging mitotherapy strategies involve isolating healthy donor mitochondria for transplantation into diseased organs to promote regeneration. This review highlights mitochondria's inherent roles in liver regeneration. New & Noteworthy Mitochondrial therapy (Mitotherapy) could potentially be the next big wave in therapeutics to preserve, supplement or replace damaged mitochondria after injury. In liver, mitotherapy should be considered to not only improve organ function but as therapeutic modality that could accelerate liver regeneration after partial hepatectomy.

Keywords:  Cell cycle; Liver Regeneration; Mitochondria; Mitochondrial Therapy

DOI:  https://doi.org/10.1152/ajpgi.00220.2022
Mol Immunol. 2023 Jan 12. pii: S0161-5890(23)00005-6. [Epub ahead of print]155 7-16

CoQ10 alleviates hepatic ischemia reperfusion injury via inhibiting NLRP3 activity and promoting Tregs infiltration.

Shaopeng Zhang, Xiaojie Gan, Ji Gao, Jie Duan, Aidong Gu, Changhao Chen.

  Hepatic ischemia-reperfusion injury (IRI) has been concerned as a main complication of liver surgery and transplantation. Previous studies show that reactive oxygen species (ROS) associated inflammation response and contribute to the liver damage during IRI. Coenzyme Q10 (CoQ10) has shown many beneficial effects on abrogating ROS production and ameliorating liver injury. This study found lower CoQ10 level in the process of liver IRI in a mouse model of hepatic IRI. Meanwhile, our results showed that CoQ10 administration significantly attenuate hepatic IRI proved by HE staining, serum ALT/AST. The NOD-like receptor protein 3 (NLRP3) inflammasome is activated by ROS which triggers the activation of inﬂammatory caspases. In this study, NLRP3 was significantly suppressed by CoQ10 while Foxp3 exhibited increased expression in liver. Furthermore, Kupffer cells (KCs) pretreated with CoQ10 under the condition of hypoxia and reoxygenation contributed to improved CD4+CD25+Foxp3+ regulatory T cells (Tregs) ratio in co-culture system. Furthermore, NLRP3 inflammasome activator treatment in vivo resulted in higher expression of caspase-1 and NLRP3 and reduction of Tregs in liver, which reversed the protection of CoQ10 in the liver injury. Taken together, our study discovered that CoQ10 can suppress NLRP3 activity in KCs and improves Foxp3+ Tregs differentiation depending on M2 macrophage polarization of KCs to ameliorate hepatic IRI.

Keywords:  CoQ10; IRI; NLRP3; ROS; Tregs

DOI:  https://doi.org/10.1016/j.molimm.2023.01.005