bims-mitper 2023-01-08 papers

bims-mitper

Biomed News

on Mitochondrial Permeabilization

Issue of 2023–01–08
seven papers selected by
Bradley Irizarry, Thomas Jefferson University

Biological properties of the BCL-2 family protein BCL-RAMBO, which regulates apoptosis, mitochondrial fragmentation, and mitophagy.
Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.
The effects of nuclear DNA mutations on mitochondrial function.
Mitochondrial DNA Mutations and Ageing.
Crosstalk between mitophagy and innate immunity in viral infection.
cGAS in nucleus: The link between immune response and DNA damage repair.
Identification of candidate genes associated with clinical onset of Alzheimer's disease.

Front Cell Dev Biol. 2022 ;10 1065702

Biological properties of the BCL-2 family protein BCL-RAMBO, which regulates apoptosis, mitochondrial fragmentation, and mitophagy.

Takao Kataoka.

  Mitochondria play an essential role in the regulation of cellular stress responses, including cell death. Damaged mitochondria are removed by fission and fusion cycles and mitophagy, which counteract cell death. BCL-2 family proteins possess one to four BCL-2 homology domains and regulate apoptosis signaling at mitochondria. BCL-RAMBO, also known as BCL2-like 13 (BCL2L13), was initially identified as one of the BCL-2 family proteins inducing apoptosis. Mitophagy receptors recruit the ATG8 family proteins MAP1LC3/GABARAP via the MAP1LC3-interacting region (LIR) motif to initiate mitophagy. In addition to apoptosis, BCL-RAMBO has recently been identified as a mitophagy receptor that possesses the LIR motif and regulates mitochondrial fragmentation and mitophagy. In the 20 years since its discovery, many important findings on BCL-RAMBO have been increasingly reported. The biological properties of BCL-RAMBO are reviewed herein.

Keywords:  BCL-RAMBO; BCL2L13; apoptosis; cell death; miRNAs; mitochondrial fragmentation; mitophagy; phosphorylation

DOI:  https://doi.org/10.3389/fcell.2022.1065702
J Biol Chem. 2023 Jan 02. pii: S0021-9258(22)01306-0. [Epub ahead of print] 102863

Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.

Elizabeth J Osterlund, Nehad Hirmiz, Dang Nguyen, James M Pemberton, Qiyin Fang, David W Andrews.

  The pro-apoptotic BH3-only endoplasmic reticulum (ER) resident protein BIK, positively regulates mitochondrial outer membrane permeabilization (MOMP), the point-of-no-return in apoptosis. It is generally accepted that BIK functions at a distance from mitochondria by binding and sequestering anti-apoptotic proteins at the ER thereby promoting ER calcium release. Although BIK is predominantly localized to the ER, we detect by FLIM-FRET microscopy, BH3 region-dependent direct binding between BIK and mitochondria-localized chimeric mutants of the anti-apoptotic proteins BCL-XL and BCL-2 in both BMK and MCF-7 cells. Direct binding was accompanied by cell-type specific differential relocalization in response to co-expression of either BIK or one of its target binding partners, BCL-XL, when co-expressed in cells. In BMK cells with genetic deletion of both BAX and BAK (BMK-DKO) our data suggest a fraction of BIK protein moves towards mitochondria in response to the expression of a mitochondria-localized BCL-XL mutant. In contrast, in MCF-7 cells our data suggest BIK is localized at both ER and mitochondria-associated endoplasmic reticulum membranes (MAMs) and binds to the mitochondria-localized BCL-XL mutant via relocalization of BCL-XL to ER and MAMs. Rather than functioning at a distance, our data suggest BIK initiates MOMP via direct interactions with ER and mitochondria-localized anti-apoptotic proteins, that occur via ER-mitochondria contact sites, and/or by relocalization of either BIK or anti-apoptotic proteins in cells.

Keywords:  BCL-2 family; BCL-2 interacting killer; BIK; FLIM-FRET; apoptosis; subcellular localization fluorescence lifetime imaging microscopy

DOI:  https://doi.org/10.1016/j.jbc.2022.102863
J Am Assoc Nurse Pract. 2023 Jan 01. 35(1): 2-4

The effects of nuclear DNA mutations on mitochondrial function.

Beth Heuer.

ABSTRACT: The multiple functions of mitochondria, including adenosine triphosphate synthesis, are controlled by the coordination of both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) genomes. Mitochondrial disorders manifest because of impairment of energy metabolism. This article focuses on mutations in two nuclear genes and their effect on mitochondrial function. Mutations in the polymerase gamma, or POLG, gene are associated with multisystemic disease processes, including Alpers Syndrome, a severe childhood-onset syndrome. Mutations in the OPA1 gene are associated with autosomal dominant optic atrophy and other neurologic, musculoskeletal, and ophthalmologic symptoms. When assessing for disorders affecting energy metabolism, sequencing of both the mtDNA genome and the nDNA whole exome sequencing is necessary.

DOI: https://doi.org/10.1097/JXX.0000000000000827
Subcell Biochem. 2023 ;102 77-98

Mitochondrial DNA Mutations and Ageing.

Julia C Whitehall, Anna L M Smith, Laura C Greaves.

  Mitochondria are subcellular organelles present in most eukaryotic cells which play a significant role in numerous aspects of cell biology. These include carbohydrate and fatty acid metabolism to generate cellular energy through oxidative phosphorylation, apoptosis, cell signalling, haem biosynthesis and reactive oxygen species production. Mitochondrial dysfunction is a feature of many human ageing tissues, and since the discovery that mitochondrial DNA mutations were a major underlying cause of changes in oxidative phosphorylation capacity, it has been proposed that they have a role in human ageing. However, there is still much debate on whether mitochondrial DNA mutations play a causal role in ageing or are simply a consequence of the ageing process. This chapter describes the structure of mammalian mitochondria, and the unique features of mitochondrial genetics, and reviews the current evidence surrounding the role of mitochondrial DNA mutations in the ageing process. It then focusses on more recent discoveries regarding the role of mitochondrial dysfunction in stem cell ageing and age-related inflammation.

Keywords:  Ageing; Cellular damage; DNA; Free radical damage; Mitochondria; Molecular damage; Mutations

DOI:  https://doi.org/10.1007/978-3-031-21410-3_4
Front Microbiol. 2022 ;13 1064045

Crosstalk between mitophagy and innate immunity in viral infection.

Cheng Fu, Nan Cao, Wenjun Liu, Zilin Zhang, Zihui Yang, Wenhui Zhu, Shuangqi Fan.

  Mitochondria are important organelles involved in cell metabolism and programmed cell death in eukaryotic cells and are closely related to the innate immunity of host cells against viruses. Mitophagy is a process in which phagosomes selectively phagocytize damaged or dysfunctional mitochondria to form autophagosomes and is degraded by lysosomes, which control mitochondrial mass and maintain mitochondrial dynamics and cellular homeostasis. Innate immunity is an important part of the immune system and plays a vital role in eliminating viruses. Viral infection causes many physiological and pathological alterations in host cells, including mitophagy and innate immune pathways. Accumulating evidence suggests that some virus promote self-replication through regulating mitophagy-mediated innate immunity. Clarifying the regulatory relationships among mitochondria, mitophagy, innate immunity, and viral infection will shed new insight for pathogenic mechanisms and antiviral strategies. This review systemically summarizes the activation pathways of mitophagy and the relationship between mitochondria and innate immune signaling pathways, and then discusses the mechanisms of viruses on mitophagy and innate immunity and how viruses promote self-replication by regulating mitophagy-mediated innate immunity.

Keywords:  innate immunity; mechanisms; mitochondria; mitophagy; viral infection

DOI:  https://doi.org/10.3389/fmicb.2022.1064045
Front Immunol. 2022 ;13 1076784

cGAS in nucleus: The link between immune response and DNA damage repair.

Jia-Xian Song, Deana Villagomes, Hongchang Zhao, Min Zhu.

  As the first barrier of host defense, innate immunity sets up the parclose to keep out external microbial or virus attacks. Depending on the type of pathogens, several cytoplasm pattern recognition receptors exist to sense the attacks from either foreign or host origins, triggering the immune response to battle with the infections. Among them, cGAS-STING is the major pathway that mainly responds to microbial DNA, DNA virus infections, or self-DNA, which mainly comes from genome instability by-product or released DNA from the mitochondria. cGAS was initially found functional in the cytoplasm, although intriguing evidence indicates that cGAS exists in the nucleus where it is involved in the DNA damage repair process. Because the close connection between DNA damage response and immune response and cGAS recognizes DNA in length-dependent but DNA sequence-independent manners, it is urgent to clear the function balance of cGAS in the nucleus versus cytoplasm and how it is shielded from recognizing the host origin DNA. Here, we outline the current conception of immune response and the regulation mechanism of cGAS in the nucleus. Furthermore, we will shed light on the potential mechanisms that are restricted to be taken away from self-DNA recognition, especially how post-translational modification regulates cGAS functions.

Keywords:  DDR; cGAS; cancer therapy; innate immunity response; post-translational modification

DOI:  https://doi.org/10.3389/fimmu.2022.1076784
Front Neurosci. 2022 ;16 1060111

Identification of candidate genes associated with clinical onset of Alzheimer's disease.

Wang Liao, Haoyu Luo, Yuting Ruan, Yingren Mai, Chongxu Liu, Jiawei Chen, Shaoqing Yang, Aiguo Xuan, Jun Liu.

   Background and objective: Alzheimer's disease (AD) is the most common type of dementia, with its pathology like beta-amyloid and phosphorylated tau beginning several years before the clinical onset. The aim is to identify genetic risk factors associated with the onset of AD.
Methods: We collected three microarray data of post-mortem brains of AD patients and the healthy from the GEO database and screened differentially expressed genes between AD and healthy control. GO/KEGG analysis was applied to identify AD-related pathways. Then we distinguished differential expressed genes between symptomatic and asymptomatic AD. Feature importance with logistic regression analysis is adopted to identify the most critical genes with symptomatic AD.
Results: Data was collected from three datasets, including 184 AD patients and 132 healthy controls. We found 66 genes to be differently expressed between AD and the control. The pathway enriched in the process of exocytosis, synapse, and metabolism and identified 19 candidate genes, four of which (VSNL1, RTN1, FGF12, and ENC1) are vital.
Conclusion: VSNL1, RTN1, FGF12, and ENC1 may be the essential genes that progress asymptomatic AD to symptomatic AD. Moreover, they may serve as genetic risk factors to identify high-risk individuals showing an earlier onset of AD.

Keywords:  Alzheimer’s disease; GEO; dementia; genes; transcriptomic analysis

DOI:  https://doi.org/10.3389/fnins.2022.1060111