bims-mikwok 2022-10-23 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2022‒10‒23
five papers selected by
Avinash N. Mukkala
University of Toronto

Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.
Parkin drives pS65-Ub turnover independently of canonical autophagy in Drosophila.
Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.
LncRNA Hnf4αos exacerbates liver ischemia/reperfusion injury in mice via Hnf4αos/Hnf4α duplex-mediated PGC1α suppression.
CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection.

EMBO Rep. 2022 Oct 18. e55191

Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.

Chao-Chieh Lin, Jin Yan, Meghan D Kapur, Kristi L Norris, Cheng-Wei Hsieh, De Huang, Nicolas Vitale, Kah-Leong Lim, Ziqiang Guan, Xiao-Fan Wang, Jen-Tsan Chi, Wei-Yuan Yang, Tso-Pang Yao.

  Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubiquitinated mitochondria activate autophagosome assembly locally to ensure efficient destruction. Here, we report that Parkin activates lipid remodeling on mitochondria targeted for autophagic destruction. Mitochondrial Parkin induces the production of phosphatidic acid (PA) and its subsequent conversion to diacylglycerol (DAG) by recruiting phospholipase D2 and activating the PA phosphatase, Lipin-1. The production of DAG requires mitochondrial ubiquitination and ubiquitin-binding autophagy receptors, NDP52 and optineurin (OPTN). Autophagic receptors, via Golgi-derived vesicles, deliver an autophagic activator, EndoB1, to ubiquitinated mitochondria. Inhibition of Lipin-1, NDP52/OPTN, or EndoB1 results in a failure to produce mitochondrial DAG, autophagosomes, and mitochondrial clearance, while exogenous cell-permeable DAG can induce autophagosome production. Thus, mitochondrial DAG production acts downstream of Parkin to enable the local assembly of autophagosomes for the efficient disposal of ubiquitinated mitochondria.

Keywords:  Lipin-1; PLD2; Parkin; diacylglycerol; mitophagy

DOI:  https://doi.org/10.15252/embr.202255191
EMBO Rep. 2022 Oct 17. e202153552

Parkin drives pS65-Ub turnover independently of canonical autophagy in Drosophila.

Joanne L Usher, Alvaro Sanchez-Martinez, Ana Terriente-Felix, Po-Lin Chen, Juliette J Lee, Chun-Hong Chen, Alexander J Whitworth.

  Parkinson's disease-related proteins, PINK1 and Parkin, act in a common pathway to maintain mitochondrial quality control. While the PINK1-Parkin pathway can promote autophagic mitochondrial turnover (mitophagy) following mitochondrial toxification in cell culture, alternative quality control pathways are suggested. To analyse the mechanisms by which the PINK1-Parkin pathway operates in vivo, we developed methods to detect Ser65-phosphorylated ubiquitin (pS65-Ub) in Drosophila. Exposure to the oxidant paraquat led to robust, Pink1-dependent pS65-Ub production, while pS65-Ub accumulates in unstimulated parkin-null flies, consistent with blocked degradation. Additionally, we show that pS65-Ub specifically accumulates on disrupted mitochondria in vivo. Depletion of the core autophagy proteins Atg1, Atg5 and Atg8a did not cause pS65-Ub accumulation to the same extent as loss of parkin, and overexpression of parkin promoted turnover of both basal and paraquat-induced pS65-Ub in an Atg5-null background. Thus, we have established that pS65-Ub immunodetection can be used to analyse Pink1-Parkin function in vivo as an alternative to reporter constructs. Moreover, our findings suggest that the Pink1-Parkin pathway can promote mitochondrial turnover independently of canonical autophagy in vivo.

Keywords:   in vivo ; Parkinson's disease; mitochondria; mitophagy; phospho-ubiquitin

DOI:  https://doi.org/10.15252/embr.202153552
EMBO J. 2022 Oct 17. e111173

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.

Hao Liu, Hualin Fan, Pengcheng He, Haixia Zhuang, Xiao Liu, Meiting Chen, Wenwei Zhong, Yi Zhang, Cien Zhen, Yanling Li, Huilin Jiang, Tian Meng, Yiming Xu, Guojun Zhao, Du Feng.

  Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1β (IL-1β) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.

Keywords:  AFG3L2; MIMP; PHB; SPG7; mtDNA

DOI:  https://doi.org/10.15252/embj.2022111173
Redox Biol. 2022 Oct 06. pii: S2213-2317(22)00270-1. [Epub ahead of print]57 102498

LncRNA Hnf4αos exacerbates liver ischemia/reperfusion injury in mice via Hnf4αos/Hnf4α duplex-mediated PGC1α suppression.

Chaoqun Wang, Hongjun Yu, Shounan Lu, Shanjia Ke, Yanan Xu, Zhigang Feng, Baolin Qian, Miaoyu Bai, Bing Yin, Xinglong Li, Yongliang Hua, Liqian Dong, Yao Li, Bao Zhang, Zhongyu Li, Dong Chen, Bangliang Chen, Yongzhi Zhou, Shangha Pan, Yao Fu, Hongchi Jiang, Dawei Wang, Yong Ma.

  LncRNAs are involved in the pathophysiologic processes of multiple diseases, but little is known about their functions in hepatic ischemia/reperfusion injury (HIRI). As a novel lncRNA, the pathogenetic significance of hepatic nuclear factor 4 alpha, opposite strand (Hnf4αos) in hepatic I/R injury remains unclear. Here, differentially expressed Hnf4αos and Hnf4α antisense RNA 1 (Hnf4α-as1) were identified in liver tissues from mouse ischemia/reperfusion models and patients who underwent liver resection surgery. Hnf4αos deficiency in Hnf4αos-KO mice led to improved liver function, alleviated the inflammatory response and reduced cell death. Mechanistically, we found a regulatory role of Hnf4αos-KO in ROS metabolism through PGC1α upregulation. Hnf4αos also promoted the stability of Hnf4α mRNA through an RNA/RNA duplex, leading to the transcriptional activation of miR-23a and miR-23a depletion was required for PGC1α function in hepatoprotective effects on HIRI. Together, our findings reveal that Hnf4αos elevation in HIRI leads to severe liver damage via Hnf4αos/Hnf4α/miR-23a axis-mediated PGC1α inhibition.

Keywords:  Hnf4αos; Ischemia/reperfusion; Liver; PGC1α; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2022.102498
Sci Adv. 2022 Oct 21. 8(42): eabo1244

CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection.

Devasena Ponnalagu, Shanna Hamilton, Shridhar Sanghvi, Diego Antelo, Neill Schwieterman, Inderjot Hansra, Xianyao Xu, Erhe Gao, John C Edwards, Shyam S Bansal, Loren E Wold, Dmitry Terentyev, Paul M L Janssen, Thomas J Hund, Mahmood Khan, Andrew R Kohut, Walter J Koch, Harpreet Singh.

Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.

DOI: https://doi.org/10.1126/sciadv.abo1244