bims-mikwok 2021-03-14 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2021‒03‒14
nine papers selected by
Avinash N. Mukkala, University of Toronto

CMLS forum reviews: mitochondrial damage control.
BOK controls apoptosis by Ca2+ transfer through ER-mitochondrial contact sites.
Layilin promotes mitochondrial fission by cyclin-dependent kinase 1 and dynamin-related protein 1 activation in HEK293T cells.
Mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC.
Balancing ER-Mitochondrial Ca2+ Fluxes in Health and Disease.
Abrogating mitochondrial ROS in neurons or astrocytes reveals cell-specific impact on mouse behaviour.
Mitochondrial Redox and TCA Cycle Metabolite Signaling in the Heart.
Mild hypothermia pretreatment extenuates liver ischemia-reperfusion injury through Rab7-mediated autophagosomes-lysosomes fusion.
Hypertonic saline solution decreases oxidative stress in liver hypothermic ischemia.

Cell Mol Life Sci. 2021 Mar 12.

CMLS forum reviews: mitochondrial damage control.

Anne Hamacher-Brady.

  Mitochondria supply cellular energy through oxidative phosphorylation and fulfill numerous additional functions that are fundamental to cellular homeostasis and stress responses. Mitochondrial malfunction, arising from inherent defects of the organelle itself, aging, or acute or chronic stress, can cause substantial damage to organismal health. For instance, mitochondrial malfunction contributes to inflammation, neurodegeneration, tumorigenesis and cardiovascular diseases. Therefore, various quality control mechanisms exist that support a functional mitochondrial organelle compartment. The CMLS Forum Reviews introduced here present a collection of articles covering select topics on basic mechanisms and pathophysiological contexts of mitochondrial damage control.

Keywords:  Apoptosis; Autophagy; Mitochondria; Mitochondrial dynamics; Mitochondrial quality control; Mitochondrial retrograde response; Mitochondrial unfolded protein response; Mitophagy; Stress signaling

DOI:  https://doi.org/10.1007/s00018-021-03804-y
Cell Rep. 2021 Mar 09. pii: S2211-1247(21)00141-8. [Epub ahead of print]34(10): 108827

BOK controls apoptosis by Ca2+ transfer through ER-mitochondrial contact sites.

Marcos A Carpio, Robert E Means, Allison L Brill, Alva Sainz, Barbara E Ehrlich, Samuel G Katz.

  Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains. Rescue of the ER-mitochondrial juxtaposition with drug-inducible interorganelle linkers reveals a kinetic disruption, which when overcome in Bok-/- cells is still insufficient to rescue thapsigargin-induced calcium transfer and apoptosis. Likewise, a BOK mutant unable to interact with IP3R restores ER-mitochondrial proximity, but not ER-mitochondrial calcium transfer, MAM protein composition, or apoptosis. This work identifies the dynamic coordination of ER-mitochondrial contact by BOK as an important control point for apoptosis.

Keywords:  BCL-2 family; BOK; IP3R; MAMs; MERCs; apoptosis; calcium; endoplasmic reticulum; mitochondria-ER contact sites; mitochondria-associated membranes

DOI:  https://doi.org/10.1016/j.celrep.2021.108827
Biochem Biophys Res Commun. 2021 Mar 03. pii: S0006-291X(21)00299-0. [Epub ahead of print]549 143-149

Layilin promotes mitochondrial fission by cyclin-dependent kinase 1 and dynamin-related protein 1 activation in HEK293T cells.

Atsuhiro Tsutiya, Mitsumi Arito, Takuma Tagashira, Masaaki Sato, Kazuki Omoteyama, Toshiyuki Sato, Naoya Suematsu, Manae S Kurokawa, Tomohiro Kato.

  OBJECT: Functions of layilin, a type 1 transmembrane protein with a C-type lectin motif, remain to be clarified. We here investigated precise intracellular localization of layilin and the location-related functions.METHODS: We used HEK293T cells to assess the co-localization of layilin with different individual organelle markers by double immunostaining. We then investigated mitochondrial morphology in layilin-knockdown (KD) conditions, also with immunostaining. Next, we measured amounts of proteins involved in regulation of mitochondrial dynamics, DRP1, pS616-DRP1, mitofusin1, mitofusin2, CDK1, pY15-CDK1, and cyclin B1, in layilin-KD cells versus control cells by Western blot. Furthermore, by using layilin-knockout (KO) cells, amounts of CDK1 and pY15-CDK1 as well as mitochondrial morphology were investigated.
RESULT: We found that layilin localized to mitochondria rather than the other organelles. Small round-shape mitochondria were observed in control cells, whereas elongated and highly connected mitochondria were observed in layilin-KD cells. Amounts of active DRP1 (pS616-DRP1) and total DRP1 were significantly smaller in layilin-KD cells than in controls. Amounts of inactive CDK1 (pY15-CDK1) were significantly larger in layilin-KD cells than in controls. No other tested molecules were significantly altered in layilin-KD cells. Amounts of inactive CDK1 were significantly larger in layilin-KO cells than in wild type (WT) cells. Small round-shape mitochondria were observed in WT cells, whereas elongated and highly connected mitochondria were observed in layilin-KO cells.
CONCLUSION: We here demonstrated that layilin played a role in the maintenance of fragmented mitochondria in mitochondrial dynamics and that this function needed CDK1 and DRP1 activation. Our data unveiled a novel function for layilin, regulation of mitochondrial dynamics.

Keywords:  CDK1; DRP1; Layilin; Mitochondria

DOI:  https://doi.org/10.1016/j.bbrc.2021.02.091
Autophagy. 2021 Mar 08. 1-10

Mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC.

Yi-Ting Liu, Danielle A Sliter, Mario K Shammas, Xiaoping Huang, Chunxin Wang, Hannah Calvelli, Dragan S Maric, Derek P Narendra.

  PINK1 and PRKN, which cause Parkinson disease when mutated, form a quality control mitophagy pathway that is well-characterized in cultured cells. The extent to which the PINK1-PRKN pathway contributes to mitophagy in vivo, however, is controversial. This is due in large part to conflicting results from studies using one of two mitophagy reporters: mt-Keima or mito-QC. Studies using mt-Keima have generally detected PINK1-PRKN mitophagy in vivo, whereas those using mito-QC generally have not. Here, we directly compared the performance of mito-QC and mt-Keima in cell culture and in mice subjected to a PINK1-PRKN activating stress. We found that mito-QC was less sensitive than mt-Keima for mitophagy, and that this difference was more pronounced for PINK1-PRKN mitophagy. These findings suggest that mito-QC's poor sensitivity may account for conflicting reports of PINK1-PRKN mitophagy in vivo and caution against using mito-QC as a reporter for PINK1-PRKN mitophagy.

Keywords:  Autophagy; PARK2; PARKIN; Parkinson; degradation; disease; mitochondria; neurodegeneration; organelle

DOI:  https://doi.org/10.1080/15548627.2021.1896924
Trends Cell Biol. 2021 Mar 04. pii: S0962-8924(21)00028-3. [Epub ahead of print]

Balancing ER-Mitochondrial Ca2+ Fluxes in Health and Disease.

Jens Loncke, Allen Kaasik, Ilya Bezprozvanny, Jan B Parys, Martijn Kerkhofs, Geert Bultynck.

  Organelles cooperate with each other to control cellular homeostasis and cell functions by forming close connections through membrane contact sites. Important contacts are present between the endoplasmic reticulum (ER), the main intracellular Ca2+-storage organelle, and the mitochondria, the organelle responsible not only for the majority of cellular ATP production but also for switching on cell death processes. Several Ca2+-transport systems focalize at these contact sites, thereby enabling the efficient transmission of Ca2+ signals from the ER toward mitochondria. This provides tight control of mitochondrial functions at the microdomain level. Here, we discuss how ER-mitochondrial Ca2+ transfers support cell function and how their dysregulation underlies, drives, or contributes to pathogenesis and pathophysiology, with a major focus on cancer and neurodegeneration but also with attention to other diseases such as diabetes and rare genetic diseases.

Keywords:  Ca(2+) signaling; MAMs; cancer; contact sites; genetic diseases; neurodegeneration

DOI:  https://doi.org/10.1016/j.tcb.2021.02.003
Redox Biol. 2021 Mar 03. pii: S2213-2317(21)00065-3. [Epub ahead of print]41 101917

Abrogating mitochondrial ROS in neurons or astrocytes reveals cell-specific impact on mouse behaviour.

Carlos Vicente-Gutierrez, Nicolo Bonora, Daniel Jimenez-Blasco, Irene Lopez-Fabuel, Georgina Bates, Michael P Murphy, Angeles Almeida, Juan P Bolaños.

  Cells naturally produce mitochondrial reactive oxygen species (mROS), but the in vivo pathophysiological significance has long remained controversial. Within the brain, astrocyte-derived mROS physiologically regulate behaviour and are produced at one order of magnitude faster than in neurons. However, whether neuronal mROS abundance differentially impacts on behaviour is unknown. To address this, we engineered genetically modified mice to down modulate mROS levels in neurons in vivo. Whilst no alterations in motor coordination were observed by down modulating mROS in neurons under healthy conditions, it prevented the motor discoordination caused by the pro-oxidant neurotoxin, 3-nitropropionic acid (3-NP). In contrast, abrogation of mROS in astrocytes showed no beneficial effect against the 3-NP insult. These data indicate that the impact of modifying mROS production on mouse behaviour critically depends on the specific cell-type where they are generated.

Keywords:  Astrocyte; In vivo; Mitochondria; Neuron; ROS; Signallling

DOI:  https://doi.org/10.1016/j.redox.2021.101917
Free Radic Biol Med. 2021 Mar 03. pii: S0891-5849(21)00139-8. [Epub ahead of print]

Mitochondrial Redox and TCA Cycle Metabolite Signaling in the Heart.

Ana Vujic, Amy N M Koo, Hiran A Prag, Thomas Krieg.

  Mitochondria are essential signaling organelles that regulate a broad range of cellular processes and thereby heart function. Multiple mechanisms participate in the communication between mitochondria and the nucleus that maintain cardiomyocyte homeostasis, including mitochondrial reactive oxygen species (ROS) and metabolic shifts in TCA cycle metabolite availability. An increased rate of ROS generation can cause irreversible damage to the cell and proposed to be a leading cause of many pathologies, including accelerated aging and heart disease. Myocardial impairments are also characterised by specific coordinated metabolic changes and dysregulated inflammatory responses. Hence, the mitochondrial respiratory chain is an important mediator between health and disease in the heart. This review will first outline the sources of ROS in the heart, mitochondrial metabolite dynamics, and provide an overview of their implications for heart disease. In addition, we will concentrate our discussion around current cardioprotective strategies relevant to mitochondrial ROS. Thorough understanding of mitochondrial signaling and the complex interplay with vital signaling pathways in the heart might allow us to develop novel therapeutic approaches to cardiovascular disease.

Keywords:  Cardiovascular disease; ROS; metabolism; mitochondria; redox signaling

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.02.041
Biochem Biophys Res Commun. 2021 Mar 04. pii: S0006-291X(21)00351-X. [Epub ahead of print]550 15-21

Mild hypothermia pretreatment extenuates liver ischemia-reperfusion injury through Rab7-mediated autophagosomes-lysosomes fusion.

Anxiong Liu, Wei Wang, Zhongshan Lu, Zhongzhong Liu, Wei Zhou, Zibiao Zhong, Qifa Ye.

  Liver ischemia-reperfusion (IR) injury is an unavoidable pathological process in transplantation, closely related to poor prognosis. To date, there has been no clear therapeutic measure. We previously reported that mild hypothermia (MH), a widely used therapy, can exert significant protective effect against liver IR injury. Among the multiple mechanisms underlying the therapeutic effect of MH, autophagy flux drew our special attention. In this study, we evaluated the role of autophagy flux in IR injury and thereby explored the relationship between MH and autophagy flux in IR injury. We developed in vivo and in vitro models for hepatic IR injury. By autophagy flux assay with Western blotting and immunofluorescence, we found that MH restricts heavy accumulation of autophagosomes (APs) during IR injury. Activation and blocking of the autophagy flux unraveled that accumulation of APs further aggravated IR injury. Further, MH reduces APs accumulation to restore autophagy flux by regulating the fusion of APs and lysosomes. Besides, MH upregulated the level of Rab7 protein expression that was seriously impaired during IR injury. Inhibition of Rab7 expression increased apoptosis of liver cells and reduced the degree of overlap between APs and lysosomes. The results were reversed upon activation of Rab7. In conclusion, MH can alleviate liver IR injury by regulating the Rab7-mediated APs-lysosomes fusion that reduces APs accumulation. This can provide a theoretical basis for the further application of MH in related clinical diseases.

Keywords:  Autophagosomes-lysosomes fusion; Autophagy flux; Ischemia-reperfusion injury; Mild hypothermia; Rab7

DOI:  https://doi.org/10.1016/j.bbrc.2021.02.125
Surgery. 2021 Mar 04. pii: S0039-6060(21)00007-6. [Epub ahead of print]

Hypertonic saline solution decreases oxidative stress in liver hypothermic ischemia.

Giolana Nunes, Estela Regina Ramos Figueira, Joel Avancini Rocha-Filho, Cinthia Lanchotte, Lucas Souto Nacif, Diego Mendes Ferreira, Vitor Carminatti Romano, Emílio Elias Abdo, Luiz Augusto Carneiro D'Albuquerque, Flavio Henrique Ferreira Galvão.

BACKGROUND: Liver ischemia reperfusion injury is still an unsolved problem in liver surgery and transplantation. In this setting, hypothermia is the gold standard method for liver preservation for transplantation. Hypertonic saline solution reduces inflammatory response with better hemodynamic recovery in several situations involving ischemia reperfusion injury. Here, we investigated the effect of hypertonic saline solution in hypothermic liver submitted to ischemia reperfusion injury.METHODS: Fifty male rats were divided into 5 groups: SHAM, WI (animals submitted to 40 minutes of partial warm liver ischemia and reperfusion), HI (animals submitted to 40 minutes hypothermic ischemia), HSPI (animals submitted to hypothermic ischemia and treated with 7.5% hypertonic saline solution preischemia), and HSPR (animals submitted to hypothermic ischemia and treated with hypertonic saline solution previously to liver reperfusion). Four hours after reperfusion, the animals were killed to collect liver and blood samples.
RESULTS: Aspartate aminotransferase and alanine aminotransferase, histologic score, and hepatocellular necrosis were significantly decreased in animals submitted to hypothermia compared with the warm ischemia group. Malondialdehyde was significantly decreased in hypothermic groups with a further decrease when hypertonic saline solution was administrated preischemia. Hypothermic groups also showed decreased interleukin-6, interleukin-10, and tumor necrosis factor-α concentrations and better recovery of bicarbonate, base excess, lactate, and glucose blood concentrations. Moreover, hypertonic saline solution preischemia was more effective at controlling serum potassium concentrations.
CONCLUSION: Hypertonic saline solution before hypothermic hepatic ischemia decreases hepatocellular oxidative stress, cytokine concentrations, and promotes better recovery of acid-base disorders secondary to liver ischemia reperfusion.

DOI: https://doi.org/10.1016/j.surg.2020.12.042