bims-mecmid 2022-02-06 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2022–02–06
sixteen papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Characterisation of cold-induced mitochondrial fission in porcine aortic endothelial cells.
Regulation of dynamin-related protein 1 (DRP1) levels modulates myoblast atrophy induced by C26 colon cancer-conditioned medium.
Regulation of Mitochondrial Dynamics by Aerobic Exercise in Cardiovascular Diseases.
Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
Dual regulating of mitochondrial fusion and Timp-3 by leflunomide and diallyl disulfide combination suppresses diethylnitrosamine-induced hepatocellular tumorigenesis in rats.
Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.
Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.
Baicalin attenuates amyloid β oligomers induced memory deficits and mitochondria fragmentation through regulation of PDE-PKA-Drp1 signalling.
A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons.
The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.
FUNDC1: A Promising Mitophagy Regulator at the Mitochondria-Associated Membrane for Cardiovascular Diseases.
Mitochondrial retrograde signaling through UCP1-mediated inhibition of the plant oxygen-sensing pathway.
ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development.
Mitochondrial distribution in the outer plexiform layer of human retina - Does it correlate with reflectivity in OCT?
Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy.

Mol Med. 2022 Jan 31. 28(1): 13

Characterisation of cold-induced mitochondrial fission in porcine aortic endothelial cells.

Leonard Quiring, Björn Walter, Niklas Lohaus, Dhanusha Schwan, Anja Rech, Andrea Dlugos, Ursula Rauen.

   BACKGROUND: Previously, we observed that hypothermia, widely used for organ preservation, elicits mitochondrial fission in different cell types. However, temperature dependence, mechanisms and consequences of this cold-induced mitochondrial fission are unknown. Therefore, we here study cold-induced mitochondrial fission in endothelial cells, a cell type generally displaying a high sensitivity to cold-induced injury.
METHODS: Porcine aortic endothelial cells were incubated at 4-25 °C in modified Krebs-Henseleit buffer (plus glucose to provide substrate and deferoxamine to prevent iron-dependent hypothermic injury).
RESULTS: Cold-induced mitochondrial fission occurred as early as after 3 h at 4 °C and at temperatures below 21 °C, and was more marked after longer cold incubation periods. It was accompanied by the formation of unusual mitochondrial morphologies such as donuts, blobs, and lassos. Under all conditions, re-fusion was observed after rewarming. Cellular ATP content dropped to 33% after 48 h incubation at 4 °C, recovering after rewarming. Drp1 protein levels showed no significant change during cold incubation, but increased phosphorylation at both phosphorylation sites, activating S616 and inactivating S637. Drp1 receptor protein levels were unchanged. Instead of increased mitochondrial accumulation of Drp1 decreased mitochondrial localization was observed during hypothermia. Moreover, the well-known Drp1 inhibitor Mdivi-1 showed only partial protection against cold-induced mitochondrial fission. The inner membrane fusion-mediating protein Opa1 showed a late shift from the long to the fusion-incompetent short isoform during prolonged cold incubation. Oma1 cleavage was not observed.
CONCLUSIONS: Cold-induced mitochondrial fission appears to occur over almost the whole temperature range relevant for organ preservation. Unusual morphologies appear to be related to fission/auto-fusion. Fission appears to be associated with lower mitochondrial function/ATP decline, mechanistically unusual, and after cold incubation in physiological solutions reversible at 37 °C.

Keywords:  Endothelium; Mitochondria; Mitochondrial dynamics; Mitochondrial fragmentation; Mitochondrial fusion; Preservation

DOI:  https://doi.org/10.1186/s10020-021-00430-z
Transl Cancer Res. 2021 Jun;10(6): 3020-3032

Regulation of dynamin-related protein 1 (DRP1) levels modulates myoblast atrophy induced by C26 colon cancer-conditioned medium.

Xiangyu Mao, Qingyang Meng, Jun Han, Lei Shen, Xiangyu Sui, Yihua Gu, Guohao Wu.

   Background: Cancer associated-cachexia, which involves progressive skeletal muscle loss, is induced by multiple factors. However, the underlying mechanism remains unclear. Dynamin-related protein 1 (DRP1), a major modulator of mitochondrial fission, has been reported to participate in muscle turnover. This study aimed to explore the role of DRP1 in muscle during the process of cancer associated-cachexia (CAC) via an in vitro model and the mechanisms involved.
Methods: C26 colon cancer cell-conditioned medium (CM) was used to incubate with C2C12 myotubes to simulate cachexia. Myotubes were then transduced with lentiviral vectors of DRP1-small interfering RNA (siRNA), DRP1 overexpression plasmid, or a control plasmid to regulate the DRP1 levels, and their diameters were assessed using a biological microscope. Furthermore, transcriptome sequencing was performed to screen the pathways involved, and real-time polymerase chain reaction (RT-PCR) was used for verification.
Results: The cachexia model was successfully established with a decreased myotube diameter and increased DRP1 expression. DRP1 knockdown significantly ameliorated myotube wasting during cachexia, while DRP1 overexpression intensified this phenomenon. Transcriptome sequencing indicated that DRP1 knockdown was associated with the activation of ribosomal biogenesis. However, PCR results showed that compared to the control, one of the ribosomal biogenesis marker's (Ubf) level was decreased by C26 CM, and DRP1 knockdown did not significantly restore its level.
Conclusions: During C26 CM-induced cachexia, DRP1 was activated, while the regulation of DRP1 levels was able to modulate the atrophy of C2C12 myotubes. The underlying mechanism of the alleviated muscle atrophy induced by DRP1 knockdown was likely associated with increased ribosomal activity.

Keywords:  Cachexia; dynamins; muscular atrophy; neoplasms; ribosomes

DOI:  https://doi.org/10.21037/tcr-21-751
Front Cardiovasc Med. 2021 ;8 788505

Regulation of Mitochondrial Dynamics by Aerobic Exercise in Cardiovascular Diseases.

Changping Gu, Jie Yan, Liang Zhao, Guanghan Wu, Yue-Lan Wang.

  Mitochondrial dynamics, including continuous biogenesis, fusion, fission, and autophagy, are crucial to maintain mitochondrial integrity, distribution, size, and function, and play an important role in cardiovascular homeostasis. Cardiovascular health improves with aerobic exercise, a well-recognized non-pharmaceutical intervention for both healthy and ill individuals that reduces overall cardiovascular disease (CVD) mortality. Increasing evidence shows that aerobic exercise can effectively regulate the coordinated circulation of mitochondrial dynamics, thus inhibiting CVD development. This review aims to illustrate the benefits of aerobic exercise in prevention and treatment of cardiovascular disease by modulating mitochondrial function.

Keywords:  aerobic exercise; cardiovascular disease; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; myocardial mitochondria

DOI:  https://doi.org/10.3389/fcvm.2021.788505
Nat Commun. 2022 Feb 03. 13(1): 651

Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.

Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

DOI: https://doi.org/10.1038/s41467-022-28272-1
Life Sci. 2022 Feb 01. pii: S0024-3205(22)00069-8. [Epub ahead of print] 120369

Dual regulating of mitochondrial fusion and Timp-3 by leflunomide and diallyl disulfide combination suppresses diethylnitrosamine-induced hepatocellular tumorigenesis in rats.

Nabil Mohie Abdel-Hamid, Shimaa A Abass, Ramadan A Eldomany, Mona A Abdel-Kareem, Sherin Zakaria.

   AIMS: Hepatocellular carcinoma (HCC) is considered one of the main causes of cancer-related death globally. Combination therapy targeting different pathways can improve the efficacy of HCC management. Mitofusin 2 (Mfn2), a mitochondrial fusion protein, and a tissue inhibitor of matrix metalloproteinase 3 (Timp-3) were found to be downregulated in various cancers, including HCC. Our study aimed to evaluate the possible antineoplastic effect of a novel combination in the treatment of HCC through targeting mitochondrial fusion and metastatic proteins.
MAIN METHODS: HCC induction was performed using a single intraperitoneal dose of diethylnitrosamine (200 mg/kg), followed by adding phenobarbital sodium (0.05%) to the drinking water for successive 18 weeks. Then, leflunomide (LF, 10 mg/kg) was administered orally for 28 days. Diallyl disulfide (DADS, 50 mg/kg) was also given orally for 28 days, either alone or in combination with LF.
KEY FINDINGS: Treatment with LF or DADS could alleviate the HCC- induced histological and biochemical variations, including liver enzyme activities (ALT, AST), alpha-fetoprotein, Bax, cyclin D1, Ki67, malondialdehyde, and reduced glutathione. They could shift the mitochondrial dynamics toward mitochondrial fusion through upregulating the expression of Mfn2 and also exhibited antimetastatic activity through upregulating the expression of Timp-3 and decreasing hepatic MMP9 content.
SIGNIFICANCE: the treatment with a combination of LF and DADS displayed a more potent effect than the treatment with each drug alone. Our results suggest that the combined use of LF and a naturally occurring DADS can be used as a promising novel combination in managing HCC.

Keywords:  Diallyl disulfide; HCC; Leflunomide; Mitochondrial fusion; Mitofusin 2; Timp-3

DOI:  https://doi.org/10.1016/j.lfs.2022.120369
Biol Chem. 2022 Jan 31.

Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.

Nupur Sharma, Christof Osman.

  The mitochondrial respiratory chain is composed of nuclear as well as mitochondrial-encoded subunits. A variety of factors mediate co-translational integration of mtDNA-encoded proteins into the inner membrane. In Saccharomyces cerevisiae, Mdm38 and Mba1 are ribosome acceptors that recruit the mitochondrial ribosome to the inner membrane, where the insertase Oxa1, facilitates membrane integration of client proteins. The protein Yme2 has previously been shown to be localized in the inner mitochondrial membrane and has been implicated in mitochondrial protein biogenesis, but its mode of action remains unclear. Here, we show that multiple copies of Yme2 assemble into a high molecular weight complex. Using a combination of bioinformatics and mutational analyses, we find that Yme2 possesses an RNA recognition motif (RRM), which faces the mitochondrial matrix and a AAA+ domain that is located in the intermembrane space. We further show that YME2 genetically interacts with MDM38, MBA1 and OXA1, which links the function of Yme2 to the mitochondrial protein biogenesis machinery.

Keywords:  MBA1; MDM38; OXA1; RRM; Walker motifs; mitoribosome

DOI:  https://doi.org/10.1515/hsz-2021-0398
J Cell Sci. 2022 Jan 31. pii: jcs.258956. [Epub ahead of print]

Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.

Qiancong Zhao, Shun Yan, Jin Lu, Danitra J Parker, Huiying Wu, Qianchuang Sun, David K Crossman, Shanrun Liu, Qin Wang, Hiromi Sesaki, Kasturi Mitra, Kexiang Liu, Kai Jiao.

  Mitochondrial dysfunction causes severe congenital cardiac abnormalities and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target mitochondrial deficiency induced inborn cardiomyopathies. Mitochondrial morphology, which is regulated by fission and fusion, plays a key role in determining mitochondrial activity. Dnm1l encodes a dynamin-related GTPase, Drp1, which is required for mitochondrial fission. To investigate the role of Drp1 on cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Dnm1l in second heart field-derived structures. Mutant cardiomyocytes in the right ventricle (RV) displayed severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the reduced cellular energy level to decreased transcription of ribosomal protein genes in cardiomyocytes. We therefore provide the first mouse genetic evidence to suggest that Drp1 is essential for RV development. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.

Keywords:  Drp1; Heart development; RP gene transcription

DOI:  https://doi.org/10.1242/jcs.258956
Front Cell Dev Biol. 2021 ;9 796128

Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.

Alfredo Cabrera-Orefice, Alisa Potter, Felix Evers, Johannes F Hevler, Sergio Guerrero-Castillo.

  Complexome profiling (CP) is a state-of-the-art approach that combines separation of native proteins by electrophoresis, size exclusion chromatography or density gradient centrifugation with tandem mass spectrometry identification and quantification. Resulting data are computationally clustered to visualize the inventory, abundance and arrangement of multiprotein complexes in a biological sample. Since its formal introduction a decade ago, this method has been mostly applied to explore not only the composition and abundance of mitochondrial oxidative phosphorylation (OXPHOS) complexes in several species but also to identify novel protein interactors involved in their assembly, maintenance and functions. Besides, complexome profiling has been utilized to study the dynamics of OXPHOS complexes, as well as the impact of an increasing number of mutations leading to mitochondrial disorders or rearrangements of the whole mitochondrial complexome. Here, we summarize the major findings obtained by this approach; emphasize its advantages and current limitations; discuss multiple examples on how this tool could be applied to further investigate pathophysiological mechanisms and comment on the latest advances and opportunity areas to keep developing this methodology.

Keywords:  complexome profiling; disease; mass spectrometry; mitochondria; oxidative phosphorylation; protein complex; protein-protein interaction (PPI); proteomics

DOI:  https://doi.org/10.3389/fcell.2021.796128
Psychopharmacology (Berl). 2022 Feb 01.

Baicalin attenuates amyloid β oligomers induced memory deficits and mitochondria fragmentation through regulation of PDE-PKA-Drp1 signalling.

Hai-Yang Yu, Ye Zhu, Xin-Li Zhang, Lei Wang, Yan-Meng Zhou, Fang-Fang Zhang, Han-Ting Zhang, Xiao-Min Zhao.

   RATIONALE: Mitochondrial fragmentation contributes to the initiation of Alzheimer's disease (AD) pathology. Baicalin plays a significant role in rescuing mitochondrial dysfunction. However, the effect of baicalin treatment on the modulation of mitochondrial fragmentation has not yet been assessed.
OBJECTIVES: The present study was designed to evaluate the effect of baicalin on memory and understand its mechanism of action.
RESULTS: Baicalin treatment significantly reversed the altered learning and memory behaviours in AD mouse model. We found that baicalin treatment significantly improved the levels of microtubule association protein-2 and enhanced the expression of synaptophysin and postsynaptic density protein 95 (PSD95). Moreover, treatment with baicalin reversed amyloid-β oligomer (AβO)-induced abnormalities in the succinate dehydrogenase complex iron sulphur subunit B (SDHB) and cytochrome c oxidase components I (COXI) and mitochondrial fragmentation in the hippocampus. Further, we found that baicalin decreased the PDE4 levels and upregulated the levels of phosphorylated Ser157 site of vasodilator-stimulated phosphoprotein (pVASPs157) and phosphorylated Ser637 site of mitochondrial dynamin-related protein 1 (pDrp1S637). Moreover, in AβO-treated HT-22 cells, H89 inhibited the effect of baicalin on PSD95, mitochondrial fragmentation, SDHB and COXI, PDE4, pVASPs157, and pDrp1S637.
CONCLUSION: The effect of baicalin on memory improvement may be due to improved synaptic plasticity, mitochondrial fragmentation, and rescue of dysfunction via the inhibition of PDE4, which leads to activation of pDrp1S637 in the AβO-induced model.

Keywords:  Alzheimer’s disease; Baicalin; Mitochondria fragmentation; PDE; PKA-pDrp1S637

DOI:  https://doi.org/10.1007/s00213-022-06076-x
Cell Mol Life Sci. 2022 Feb 04. 79(2): 120

A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons.

Noah Tjiang, Hans Zempel.

  Loss of neuronal polarity and missorting of the axonal microtubule-associated-protein TAU are hallmarks of Alzheimer's disease (AD) and related tauopathies. Impairment of mitochondrial function is causative for various mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is unclear. The axon-initial-segment (AIS) is vital for maintaining neuronal polarity, action potential generation, and-here important-TAU-sorting. Here, we investigate the role of mitochondria in the AIS for maintenance of TAU cellular polarity. Using not only global and local mitochondria impairment via inhibitors of the respiratory chain and a locally activatable protonophore/uncoupler, but also live-cell-imaging and photoconversion methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived forebrain/cortical neurons, and assessed somatic presence of TAU. Global application of mitochondrial toxins efficiently induced tauopathy-like TAU-missorting, indicating involvement of mitochondria in TAU-polarity. Mitochondria show a biased distribution within the AIS, with a proximal cluster and relative absence in the central AIS. The mitochondria of this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Locally constricted impairment of the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Mechanistically, mitochondrial impairment sufficient to induce TAU-missorting results in decreases of calcium oscillation but increases in baseline calcium, yet chelating intracellular calcium did not prevent mitochondrial impairment-induced TAU-missorting. Stabilizing microtubules via taxol prevented TAU-missorting, hinting towards a role for impaired microtubule dynamics in mitochondrial-dysfunction-induced TAU-missorting. We provide evidence that the mitochondrial distribution within the proximal axon is biased towards the proximal AIS and that proper function of this newly described mitochondrial cluster may be essential for the maintenance of TAU polarity. Mitochondrial impairment may be an upstream event in and therapeutic target for AD/tauopathy.

Keywords:  Alzheimer's disease; Axon initial segment/AIS; Live-cell-imaging; Microtubule; Mitochondria; Mitochondriopathy; Neuron; Neuronal cell polarity; TAU; Tauopathy

DOI:  https://doi.org/10.1007/s00018-022-04150-3
Mol Cell. 2022 Jan 28. pii: S1097-2765(22)00008-9. [Epub ahead of print]

The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.

Katia Cosentino, Vanessa Hertlein, Andreas Jenner, Timo Dellmann, Milos Gojkovic, Aida Peña-Blanco, Shashank Dadsena, Noel Wajngarten, John S H Danial, Jervis Vermal Thevathasan, Markus Mund, Jonas Ries, Ana J Garcia-Saez.

  BAX and BAK are key apoptosis regulators that mediate the decisive step of mitochondrial outer membrane permeabilization. However, the mechanism by which they assemble the apoptotic pore remains obscure. Here, we report that BAX and BAK present distinct oligomerization properties, with BAK organizing into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers that continue to grow during apoptosis. As a result, BAX and BAK regulate each other as they co-assemble into the same apoptotic pores, which we visualize. The relative availability of BAX and BAK molecules thereby determines the growth rate of the apoptotic pore and the relative kinetics by which mitochondrial contents, most notably mtDNA, are released. This feature of BAX and BAK results in distinct activation kinetics of the cGAS/STING pathway with implications for mtDNA-mediated paracrine inflammatory signaling.

Keywords:  AFM; BAK; BAX; BCL-2; inflammatory cell death; membrane pore; mitochondria; pore-forming protein; single-molecule imaging; super-resolution microscopy

DOI:  https://doi.org/10.1016/j.molcel.2022.01.008
Front Cell Dev Biol. 2021 ;9 788634

FUNDC1: A Promising Mitophagy Regulator at the Mitochondria-Associated Membrane for Cardiovascular Diseases.

Guoyong Li, Junli Li, Ruochen Shao, Jiahao Zhao, Mao Chen.

  Mitochondrial autophagy (or mitophagy) regulates the mitochondrial network and function to contribute to multiple cellular processes. The protective effect of homeostatic mitophagy in cardiovascular diseases (CVDs) has attracted increasing attention. FUN14 domain containing 1 (FUNDC1), an identified mitophagy receptor, plays an essential role in CVDs. Different expression levels of FUNDC1 and its phosphorylated state at different sites alleviate or exacerbate hypoxia and ischemia/reperfusion injury, cardiac hypertrophy, or metabolic damage through promotion or inhibition of mitophagy. In addition, FUNDC1 can be enriched at contact sites between mitochondria and the endoplasmic reticulum (ER), determining the formation of mitochondria-associated membranes (MAMs) that regulate cellular calcium (Ca2+) homeostasis and mitochondrial dynamics to prevent heart dysfunction. Moreover, FUNDC1 has also been involved in inflammatory cardiac diseases such as septic cardiomyopathy. In this review, we collect and summarize the evidence on the roles of FUNDC1 exclusively in various CVDs, describing its interactions with different cellular organelles, its involvement in multiple cellular processes, and its associated signaling pathways. FUNDC1 may become a promising therapeutic target for the prevention and management of various CVDs.

Keywords:  FUNDC1; LC3; MAM; cardiovascular diseases; mitophagy

DOI:  https://doi.org/10.3389/fcell.2021.788634
Curr Biol. 2022 Jan 28. pii: S0960-9822(22)00048-3. [Epub ahead of print]

Mitochondrial retrograde signaling through UCP1-mediated inhibition of the plant oxygen-sensing pathway.

Pedro Barreto, Charlene Dambire, Gunjan Sharma, Jorge Vicente, Rory Osborne, Juliana Yassitepe, Daniel J Gibbs, Ivan G Maia, Michael J Holdsworth, Paulo Arruda.

  Mitochondrial retrograde signaling is an important component of intracellular stress signaling in eukaryotes. UNCOUPLING PROTEIN (UCP)1 is an abundant plant inner-mitochondrial membrane protein with multiple functions including uncoupled respiration and amino-acid transport1,2 that influences broad abiotic stress responses. Although the mechanism(s) through which this retrograde function acts is unknown, overexpression of UCP1 activates expression of hypoxia (low oxygen)-associated nuclear genes.3,4 Here we show in Arabidopsis thaliana that UCP1 influences nuclear gene expression and physiological response by inhibiting the cytoplasmic PLANT CYSTEINE OXIDASE (PCO) branch of the PROTEOLYSIS (PRT)6 N-degron pathway, a major mechanism of oxygen and nitric oxide (NO) sensing.5 Overexpression of UCP1 (UCP1ox) resulted in the stabilization of an artificial PCO N-degron pathway substrate, and stability of this reporter protein was influenced by pharmacological interventions that control UCP1 activity. Hypoxia and salt-tolerant phenotypes observed in UCP1ox lines resembled those observed for the PRT6 N-recognin E3 ligase mutant prt6-1. Genetic analysis showed that UCP1 regulation of hypoxia responses required the activity of PCO N-degron pathway ETHYLENE RESPONSE FACTOR (ERF)VII substrates. Transcript expression analysis indicated that UCP1 regulation of hypoxia-related gene expression is a normal component of seedling development. Our results show that mitochondrial retrograde signaling represses the PCO N-degron pathway, enhancing substrate function, thus facilitating downstream stress responses. This work reveals a novel mechanism through which mitochondrial retrograde signaling influences nuclear response to hypoxia by inhibition of an ancient cytoplasmic pathway of eukaryotic oxygen sensing.

Keywords:  ERFVII; N-degron pathway; UCP1; abiotic stress; mitochondria; oxygen sensing; retrograde signaling

DOI:  https://doi.org/10.1016/j.cub.2022.01.037
J Exp Clin Cancer Res. 2022 Jan 29. 41(1): 43

ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development.

Liwei Lang, Reid Loveless, Juan Dou, Tiffany Lam, Alex Chen, Fang Wang, Li Sun, Jakeline Juarez, Zhaohui Steve Qin, Nabil F Saba, Chloe Shay, Yong Teng.

   BACKGROUND: Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined.
METHODS: We used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice.
RESULTS: ATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment.
CONCLUSIONS: These findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics.

Keywords:  ATAD3A; HNSCC; Mitochondrial ERK1/2; RAS; VDAC1; WA dead mutant

DOI:  https://doi.org/10.1186/s13046-022-02274-9
J Vis. 2022 Feb 01. 22(3): 2

Mitochondrial distribution in the outer plexiform layer of human retina - Does it correlate with reflectivity in OCT?

Deepayan Kar, Yeon Jin Kim, Orin Packer, Dennis M Dacey, Christine A Curcio.

Mitochondria are organelles essential for cellular metabolism that also contribute reflectivity to optical coherence tomography (OCT) via Mie scattering. To find reflectivity sources, we assessed mitochondrial distribution of outer plexiform layer (OPL) using comprehensive volume electron microscopy. Parafoveal retina of a 21-year-old male donor was subject to serial block-face scanning electron microscopy in 5×5×50 nm³ voxels. A convolutional neural network (U-Net) was used to train and generate a deep learning model from manually annotated mitochondria ground truth (Dragonfly 2020.1, Object Research Systems). Using this model, mitochondrial volume and occupancy were calculated as a function of retinal depth and plotted as a longitudinal profile. Photoreceptor terminals contained clusters of ovoid mitochondria. Dendrites of bipolar neurons exhibited long and slender mitochondria. The OPL mitochondrial distribution had three layers of higher density (photoreceptor terminals, bipolar/ horizontal processes, neuropil at the border of inner nuclear layer) interleaved by two bands of lower mitochondrial occupancy (8.5-13.8%). Mitochondria occupied <1% of the Henle fiber. Automated segmentation yielded exceptional performance vs ground truth (Dice coefficient=0.96). Evidence of multilaminar distribution of mitochondria in the OPL support hypothesis of a subcellular origin of OCT reflectivity bands. Correlative studies using AO-OCT is currently under ongoing investigation.

DOI: https://doi.org/10.1167/jov.22.3.2
Front Cardiovasc Med. 2021 ;8 822969

Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy.

Dan Yang, Han-Qing Liu, Fang-Yuan Liu, Zhen Guo, Peng An, Ming-Yu Wang, Zheng Yang, Di Fan, Qi-Zhu Tang.

  Cardiac hypertrophy, a stereotypic cardiac response to increased workload, ultimately progresses to severe contractile dysfunction and uncompensated heart failure without appropriate intervention. Sustained cardiac overload inevitably results in high energy consumption, thus breaking the balance between mitochondrial energy supply and cardiac energy demand. In recent years, accumulating evidence has indicated that mitochondrial dysfunction is implicated in pathological cardiac hypertrophy. The significant alterations in mitochondrial energetics and mitochondrial proteome composition, as well as the altered expression of transcripts that have an impact on mitochondrial structure and function, may contribute to the initiation and progression of cardiac hypertrophy. This article presents a summary review of the morphological and functional changes of mitochondria during the hypertrophic response, followed by an overview of the latest research progress on the significant modulatory roles of mitochondria in cardiac hypertrophy. Our article is also to summarize the strategies of mitochondria-targeting as therapeutic targets to treat cardiac hypertrophy.

Keywords:  cardiac hypertrophy; mitochondria; mitophagy; regulatory mechanisms; therapeutic strategies

DOI:  https://doi.org/10.3389/fcvm.2021.822969