bims-midtic 2023-07-09 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023–07–09
thirty papers selected by
Omkar Joshi, Turku Bioscience

Mitochondria- and ER-associated actin are required for mitochondrial fusion.
An Improved Method to Isolate Mitochondrial Contact Sites.
Mitochondrial quality control: prime targets for antiviral therapy?
Impaired mitochondrial dynamics and removal of the damaged mitochondria in diabetic retinopathy.
Mitochondrial regulation of local supply of energy in neurons.
Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium.
Obesity-dependent increase in RalA activity disrupts mitochondrial dynamics in white adipocytes.
ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein.
Shaping mitochondria through fed-fast and circadian cycles.
Membrane insertases at a glance.
Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.
MFN2 deficiency promotes cardiac response to hypobaric hypoxia by reprogramming cardiomyocyte metabolism.
MSCs Deliver Hypoxia-Treated Mitochondria Reprogramming Acinar Metabolism to Alleviate Severe Acute Pancreatitis Injury.
Mitochondria and the cell cycle in budding yeast.
Mitochondrial dysfunction in the offspring of obese mothers and it's transmission through damaged oocyte mitochondria: Integration of mechanisms.
Ultrastructural analysis reveals mitochondrial placement independent of synapse placement in fine caliber C. elegans neurons.
CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.
To eat or not to eat mitochondria? How do host cells cope with mitophagy upon bacterial infection?
Inhibition of TMEM16A improves cisplatin-induced acute kidney injury via preventing DRP1-mediated mitochondrial fission.
Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.
Mitochondria-associated regulation in adipose tissues and potential reagents for obesity intervention.
Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis.
The variable domain from the mitochondrial fission mechanoenzyme Drp1 promotes liquid-liquid phase separation.
A new microfluidic model to study dendritic remodeling and mitochondrial dynamics during axonal regeneration of adult zebrafish retinal neurons.
Mitochondria in endothelial cells angiogenesis and function: current understanding and future perspectives.
Photo-Lipids: Light-Sensitive Nano-Switches To Control Membrane Properties.
Restoration of mitochondrial function by Spirulina polysaccharide via upregulated SOD2 in aging fibroblasts.
Multicomponent regulation of actin barbed end assembly by twinfilin, formin and capping protein.
Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target.
Depleted Hexokinase1 and lack of AMPKα activation favor OXPHOS-dependent energetics in Retinoblastoma tumors.

bioRxiv. 2023 Jun 13. pii: 2023.06.13.544768. [Epub ahead of print]

Mitochondria- and ER-associated actin are required for mitochondrial fusion.

Priya Gatti, Cara Schiavon, Uri Manor, Marc Germain.

Mitochondria play a crucial role in the regulation of cellular metabolism and signalling. Mitochondrial activity is modulated by the processes of mitochondrial fission and fusion, which are required to properly balance respiratory and metabolic functions, transfer material between mitochondria, and remove damaged or defective mitochondria. Mitochondrial fission occurs at sites of contact between the endoplasmic reticulum (ER) and mitochondria, and is dependent on the formation of mitochondria- and ER-associated actin filaments that drive the recruitment and activation of the fission GTPase DRP1. On the other hand, the role of mitochondria- and ER-associated actin filaments in mitochondrial fusion remains unknown. Here we show that preventing the formation of actin filaments on either mitochondria or the ER using organelle-targeted Disassembly-promoting, encodable Actin tools (DeActs) blocks both mitochondrial fission and fusion. We show that fusion but not fission is dependent on Arp2/3, and both fission and fusion are dependent on INF2 formin-dependent actin polymerization. Together, our work introduces a novel method for perturbing organelle-associated actin filaments, and demonstrates a previously unknown role for mitochondria- and ER-associated actin in mitochondrial fusion.

DOI: https://doi.org/10.1101/2023.06.13.544768
J Vis Exp. 2023 06 16.

An Improved Method to Isolate Mitochondrial Contact Sites.

Siavash Khosravi, Johanna Frickel, Max E Harner.

Mitochondria are present in virtually all eukaryotic cells and perform essential functions that go far beyond energy production, for instance, the synthesis of iron-sulfur clusters, lipids, or proteins, Ca2+ buffering, and the induction of apoptosis. Likewise, mitochondrial dysfunction results in severe human diseases such as cancer, diabetes, and neurodegeneration. In order to perform these functions, mitochondria have to communicate with the rest of the cell across their envelope, which consists of two membranes. Therefore, these two membranes have to interact constantly. Proteinaceous contact sites between the mitochondrial inner and outer membranes are essential in this respect. So far, several contact sites have been identified. In the method described here, Saccharomyces cerevisiae mitochondria are used to isolate contact sites and, thus, identify candidates that qualify for contact site proteins. We used this method to identify the mitochondrial contact site and cristae organizing system (MICOS) complex, one of the major contact site-forming complexes in the mitochondrial inner membrane, which is conserved from yeast to humans. Recently, we further improved this method to identify a novel contact site consisting of Cqd1 and the Por1-Om14 complex.

DOI: https://doi.org/10.3791/65444
Trends Pharmacol Sci. 2023 Jul 04. pii: S0165-6147(23)00133-5. [Epub ahead of print]

Mitochondrial quality control: prime targets for antiviral therapy?

Yijin Wang, Peicong Ji, Qiuwei Pan.

Mitochondrial quality control (MQC) plays a crucial role in maintaining mitochondrial health. Mitochondrial dynamics and mitophagy are two intricate processes of the MQC machinery acting at the organelle level to orchestrate mitochondrial homeostasis. Here, we discuss how viruses perturb these two processes to facilitate their infections and emphasize the rationale and challenges of therapeutically targeting MQC for treating viral diseases.

DOI: https://doi.org/10.1016/j.tips.2023.06.006
Front Endocrinol (Lausanne). 2023 ;14 1160155

Impaired mitochondrial dynamics and removal of the damaged mitochondria in diabetic retinopathy.

Kumari Alka, Jay Kumar, Renu A Kowluru.

   Introduction: Mitochondrial dynamic plays a major role in their quality control, and the damaged mitochondrial components are removed by autophagy. In diabetic retinopathy, mitochondrial fusion enzyme, mitofusin 2 (Mfn2), is downregulated and mitochondrial dynamic is disturbed resulting in depolarized and dysfunctional mitochondria. Our aim was to investigate the mechanism of inhibition of Mfn2, and its role in the removal of the damaged mitochondria, in diabetic retinopathy.
Methods: Using human retinal endothelial cells, effect of high glucose (20mM) on the GTPase activity of Mfn2 and its acetylation were determined. Role of Mfn2 in the removal of the damaged mitochondria was confirmed by regulating its acetylation, or by Mfn2 overexpression, on autophagosomes- autolysosomes formation and the mitophagy flux.
Results: High glucose inhibited GTPase activity and increased acetylation of Mfn2. Inhibition of acetylation, or Mfn2 overexpression, attenuated decrease in GTPase activity and mitochondrial fragmentation, and increased the removal of the damaged mitochondria. Similar phenomenon was observed in diabetic mice; overexpression of sirtuin 1 (a deacetylase) ameliorated diabetes-induced inhibition of retinal Mfn2 and facilitated the removal of the damaged mitochondria.
Conclusions: Acetylation of Mfn2 has dual roles in mitochondrial homeostasis in diabetic retinopathy, it inhibits GTPase activity of Mfn2 and increases mitochondrial fragmentation, and also impairs removal of the damaged mitochondria. Thus, protecting Mfn2 activity should maintain mitochondrial homeostasis and inhibit the development/progression of diabetic retinopathy.

Keywords:  diabetic retinopathy; mitochondria; mitochondrial dynamics; mitofusin; mitophagy; retina

DOI:  https://doi.org/10.3389/fendo.2023.1160155
Curr Opin Neurobiol. 2023 Jun 29. pii: S0959-4388(23)00072-7. [Epub ahead of print]81 102747

Mitochondrial regulation of local supply of energy in neurons.

Guillermo López-Doménech, Josef T Kittler.

Brain computation is metabolically expensive and requires the supply of significant amounts of energy. Mitochondria are highly specialized organelles whose main function is to generate cellular energy. Due to their complex morphologies, neurons are especially dependent on a set of tools necessary to regulate mitochondrial function locally in order to match energy provision with local demands. By regulating mitochondrial transport, neurons control the local availability of mitochondrial mass in response to changes in synaptic activity. Neurons also modulate mitochondrial dynamics locally to adjust metabolic efficiency with energetic demand. Additionally, neurons remove inefficient mitochondria through mitophagy. Neurons coordinate these processes through signalling pathways that couple energetic expenditure with energy availability. When these mechanisms fail, neurons can no longer support brain function giving rise to neuropathological states like metabolic syndromes or neurodegeneration.

DOI: https://doi.org/10.1016/j.conb.2023.102747
Eur J Med Res. 2023 Jul 01. 28(1): 209

Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium.

Chaoshuang Ye, Pei Chen, Bingning Xu, Yang Jin, Yongchao Pan, Tianyu Wu, Yongjiang Du, Jingxia Mao, Ruijin Wu.

  Mitochondria play a pivotal role in physiological and metabolic function of the cell. Mitochondrial dynamics orchestrate mitochondrial function and morphology, involving fission and fusion as well as ultrastructural remodeling. Mounting evidence unravels the close link between mitochondria and endometriosis. However, how mitochondrial architecture changes through fission and fusion in eutopic and ectopic tissues of women with ovarian endometriosis remains unknown. We detected the expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium in ovarian endometriosis. The results showed that the expression of DRP1 and LCLAT1 was upregulated in eutopic endometrial stromal cells (ESCs), and the expression of DRP1, OPA1, MFN1, MFN2, and LCLAT1 was significantly downregulated in ectopic ESCs, and reduced number of mitochondria, wider cristae width and narrower cristae junction width was observed, but there was no difference in cell survival rate. The altered mitochondrial dynamics and morphology might, respectively, provide an advantage for migration and adhesion in eutopic ESCs and be the adaptive response in ectopic endometrial cells to survive under hypoxic and oxidative stress environment.

Keywords:  Cristae; Endometriosis; Fission; Fusion; Mitochondria; Mitochondrial morphology

DOI:  https://doi.org/10.1186/s40001-023-01180-w
Res Sq. 2023 Jun 02. pii: rs.3.rs-2923510. [Epub ahead of print]

Obesity-dependent increase in RalA activity disrupts mitochondrial dynamics in white adipocytes.

Wenmin Xia, Preethi Veeragandham, Yu Cao, Yayun Xu, Torrey Rhyne, Jiaxin Qian, Chao-Wei Hung, Peng Zhao, Ying Jones, Hui Gao, Christopher Liddle, Ruth Yu, Michael Downes, Ronald Evans, Mikael Ryden, Martin Wabitsch, Shannon Reilly, Jianfeng Huang, Alan Saltiel.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance, and fatty liver disease. Here we report that mitochondria undergo fragmentation and reduced oxidative capacity specifically in inguinal white adipose tissue after feeding mice high fat diet (HFD) by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes from mice fed HFD. Targeted deletion of Rala in white adipocytes prevents the obesity-induced fragmentation of mitochondria and produces mice resistant to HFD-induced weight gain via increased fatty acid oxidation. As a result, these mice also exhibit improved glucose tolerance and liver function. In vitro mechanistic studies revealed that RalA suppresses mitochondrial oxidative function in adipocytes by increasing fission through reversing the protein kinase A-catalyzed inhibitory Ser 637 phosphorylation of the mitochondrial fission protein Drp1. Active RalA recruits protein phosphatase 2A (PP2Aa) to specifically dephosphorylate this inhibitory site on Drp1, activating the protein, thus increasing mitochondrial fission. Adipose tissue expression of the human homolog of Drp1, DNML1 , is positively correlated with obesity and insulin resistance in patients. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics towards excessive fission, contributing to weight gain and related metabolic dysfunction.

DOI: https://doi.org/10.21203/rs.3.rs-2923510/v1
EMBO Rep. 2023 Jul 04. e57499

ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein.

Leonora Szabo, Nadia Cummins, Paolo Paganetti, Alex Odermatt, Andreas Papassotiropoulos, Celeste Karch, Jürgen Götz, Anne Eckert, Amandine Grimm.

  Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism.

Keywords:  GSK3β; cholesterol; endoplasmic reticulum; mitochondria; tau protein

DOI:  https://doi.org/10.15252/embr.202357499
Biochem J. 2023 Jul 12. 480(13): 909-919

Shaping mitochondria through fed-fast and circadian cycles.

Subhash Khatri, Rubina Kazi, Ullas Kolthur-Seetharam.

  Energy and metabolic homeostasis at the level of the whole body are dictated by the balance between nutrient intake/utilization, bioenergetic potential, and energy expenditure, which are tightly coupled with fed/fast cycles and circadian oscillation. Emerging literature has highlighted the importance of each of these mechanisms that are essential to maintain physiological homeostasis. Lifestyle changes predominantly associated with altered fed-fast and circadian cycles are well established to affect systemic metabolism and energetics, and hence contribute to pathophysiological states. Therefore, it is not surprising that mitochondria have emerged as being pivotal in maintaining physiological homeostasis through daily oscillations/fluctuations in nutrient inputs and light-dark/sleep-wake cycles. Moreover, given the inherent association between mitochondrial dynamics/morphology and functions, it is important to understand the phenomenological and mechanistic underpinnings of fed-fast and circadian cycles dependent remodeling of mitochondria. In this regard, we have summarized the current status of the field in addition to providing a perspective vis-a-vis the complexity of cell-autonomous and non-cell-autonomous signals that dictate mitochondrial dynamics. We also highlight the lacunae besides speculating on prospective efforts that will possibly redefine our insights into the diurnal orchestration of fission/fusion events, which are ultimately coupled to the mitochondrial output.

Keywords:  circadian clock; fed–fast cycles; fission/fusion; metabolic sensing; mitochondrial biogenesis; mitochondrial functions

DOI:  https://doi.org/10.1042/BCJ20220378
J Cell Sci. 2023 Jul 01. pii: jcs261219. [Epub ahead of print]136(13):

Membrane insertases at a glance.

Büsra Kizmaz, Johannes M Herrmann.

  Protein translocases, such as the bacterial SecY complex, the Sec61 complex of the endoplasmic reticulum (ER) and the mitochondrial translocases, facilitate the transport of proteins across membranes. In addition, they catalyze the insertion of integral membrane proteins into the lipid bilayer. Several membrane insertases cooperate with these translocases, thereby promoting the topogenesis, folding and assembly of membrane proteins. Oxa1 and BamA family members serve as core components in the two major classes of membrane insertases. They facilitate the integration of proteins with α-helical transmembrane domains and of β-barrel proteins into lipid bilayers, respectively. Members of the Oxa1 family were initially found in the internal membranes of bacteria, mitochondria and chloroplasts. Recent studies, however, also identified several Oxa1-type insertases in the ER, where they serve as catalytically active core subunits in the ER membrane protein complex (EMC), the guided entry of tail-anchored (GET) and the GET- and EMC-like (GEL) complex. The outer membrane of bacteria, mitochondria and chloroplasts contain β-barrel proteins, which are inserted by members of the BamA family. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of these different types of membrane insertases and discuss their function.

Keywords:  BAM complex; EMC complex; GET complex; Membrane insertases; Oxa1; Protein biogenesis; Translocases; YidC; β-barrel proteins

DOI:  https://doi.org/10.1242/jcs.261219
Biochim Biophys Acta Mol Basis Dis. 2023 Jun 29. pii: S0925-4439(23)00164-3. [Epub ahead of print]1869(7): 166798

Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.

Jasvinder Singh Bhatti, Satinder Kaur, Jayapriya Mishra, Harikrishnareddy Dibbanti, Arti Singh, Arubala P Reddy, Gurjit Kaur Bhatti, P Hemachandra Reddy.

  Alzheimer's disease (AD) is a neurodegenerative disease that manifests its pathology through synaptic damage, mitochondrial abnormalities, microRNA deregulation, hormonal imbalance, increased astrocytes & microglia, accumulation of amyloid β (Aβ) and phosphorylated Tau in the brains of AD patients. Despite extensive research, the effective treatment of AD is still unknown. Tau hyperphosphorylation and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline in patients with AD. Mitochondrial dysfunction is evidenced by enhanced mitochondrial fragmentation, impaired mitochondrial dynamics, mitochondrial biogenesis and defective mitophagy in AD. Hence, targeting mitochondrial proteins might be a promising therapeutic strategy in treating AD. Recently, dynamin-related protein 1 (Drp1), a mitochondrial fission protein, has gained attention due to its interactions with Aβ and hyperphosphorylated Tau, altering mitochondrial morphology, dynamics, and bioenergetics. These interactions affect ATP production in mitochondria. A reduction in Drp1 GTPase activity protects against neurodegeneration in AD models. This article provides a comprehensive overview of Drp1's involvement in oxidative damage, apoptosis, mitophagy, and axonal transport of mitochondria. We also highlighted the interaction of Drp1 with Aβ and Tau, which may contribute to AD progression. In conclusion, targeting Drp1 could be a potential therapeutic approach for preventing AD pathology.

Keywords:  Alzheimer's disease; Amyloid beta; Mitochondria; Protein folding; Tau hyperphosphorylation

DOI:  https://doi.org/10.1016/j.bbadis.2023.166798
Acta Physiol (Oxf). 2023 Jul 04. e14018

MFN2 deficiency promotes cardiac response to hypobaric hypoxia by reprogramming cardiomyocyte metabolism.

Ru Zhang, Ailin Yang, Lin Zhang, Linjie He, Xiaoming Gu, Caiyong Yu, Zhenxing Lu, Chuang Wang, Feng Zhou, Fei Li, Lele Ji, Jinliang Xing, Haitao Guo.

   AIM: Under hypobaric hypoxia (HH), the heart triggers various defense mechanisms including metabolic remodeling against lack of oxygen. Mitofusin 2 (MFN2), located at the mitochondrial outer membrane, is closely involved in the regulation of mitochondrial fusion and cell metabolism. To date, however, the role of MFN2 in cardiac response to HH has not been explored.
METHODS: Loss- and gain-of-function approaches were used to investigate the role of MFN2 in cardiac response to HH. In vitro, the function of MFN2 in the contraction of primary neonatal rat cardiomyocytes under hypoxia was examined. Non-targeted metabolomics and mitochondrial respiration analyses, as well as functional experiments were performed to explore underlying molecular mechanisms.
RESULTS: Our data demonstrated that, following 4 weeks of HH, cardiac-specific MFN2 knockout (MFN2 cKO) mice exhibited significantly better cardiac function than control mice. Moreover, restoring the expression of MFN2 clearly inhibited the cardiac response to HH in MFN2 cKO mice. Importantly, MFN2 knockout significantly improved cardiac metabolic reprogramming during HH, resulting in reduced capacity for fatty acid oxidation (FAO) and oxidative phosphorylation, and increased glycolysis and ATP production. In vitro data showed that down-regulation of MFN2 promoted cardiomyocyte contractility under hypoxia. Interestingly, increased FAO through palmitate treatment decreased contractility of cardiomyocyte with MFN2 knockdown under hypoxia. Furthermore, treatment with mdivi-1, an inhibitor of mitochondrial fission, disrupted HH-induced metabolic reprogramming and subsequently promoted cardiac dysfunction in MFN2-knockout hearts.
CONCLUSION: Our findings provide the first evidence that down-regulation of MFN2 preserves cardiac function in chronic HH by promoting cardiac metabolic reprogramming.

Keywords:  MFN2; cardiac response; hypobaric hypoxia; metabolic reprogramming; mitochondrial fusion

DOI:  https://doi.org/10.1111/apha.14018
Adv Sci (Weinh). 2023 Jul 06. e2207691

MSCs Deliver Hypoxia-Treated Mitochondria Reprogramming Acinar Metabolism to Alleviate Severe Acute Pancreatitis Injury.

Zhengyu Hu, Dongyan Wang, Jian Gong, Yan Li, Zhilong Ma, Tingyi Luo, Xuyang Jia, Yihai Shi, Zhenshun Song.

  Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti-inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia-treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury-inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.

Keywords:  cargocytes; mesenchymal stem cells; metabolic reprogramming; mitochondria transfer; severe acute pancreatitis

DOI:  https://doi.org/10.1002/advs.202207691
Int J Biochem Cell Biol. 2023 Jul 05. pii: S1357-2725(23)00083-3. [Epub ahead of print] 106444

Mitochondria and the cell cycle in budding yeast.

Ana Cláudia Leite, Vítor Costa, Clara Pereira.

  As centers for energy production and essential biosynthetic activities, mitochondria are vital for cell growth and proliferation. Accumulating evidence suggests an integrated regulation of these organelles and the nuclear cell cycle in distinct organisms. In budding yeast, a well-established example of this coregulation is the coordinated movement and positional control of mitochondria during the different phases of the cell cycle. The molecular determinants involved in the inheritance of the fittest mitochondria by the bud also seem to be cell cycle-regulated. In turn, loss of mtDNA or defects in mitochondrial structure or inheritance often lead to a cell cycle delay or arrest, indicating that mitochondrial function can also regulate cell cycle progression, possibly through the activation of cell cycle checkpoints. The up-regulation of mitochondrial respiration at G2/M, presumably to fulfil energetic requirements for progression at this phase, also supports a mitochondria-cell cycle interplay. Cell cycle-linked mitochondrial regulation is accomplished at the transcription level and through post-translational modifications, predominantly protein phosphorylation. Here, we address mitochondria-cell cycle interactions in the yeast Saccharomyces cerevisiae and discuss future challenges in the field.

Keywords:  bioenergetics; cell cycle; inheritance; mitochondria; quality control; signaling

DOI:  https://doi.org/10.1016/j.biocel.2023.106444
Biochim Biophys Acta Mol Basis Dis. 2023 Jul 04. pii: S0925-4439(23)00168-0. [Epub ahead of print] 166802

Mitochondrial dysfunction in the offspring of obese mothers and it's transmission through damaged oocyte mitochondria: Integration of mechanisms.

A L Elías-López, O Vázquez-Mena, A N Sferruzzi-Perri.

  In vivo and in vitro studies demonstrate that mitochondria in the oocyte, are susceptible to damage by suboptimal pre/pregnancy conditions, such as obesity. These suboptimal conditions have been shown to induce mitochondrial dysfunction (MD) in multiple tissues of the offspring, suggesting that mitochondria of oocytes that pass from mother to offspring, can carry information that can programme mitochondrial and metabolic dysfunction of the next generation. They also suggest that transmission of MD could increase the risk of obesity and other metabolic diseases in the population inter- and trans-generationally. In this review, we examined whether MD observed in offspring tissues of high energetic demand, is the result of the transmission of damaged mitochondria from obese mothers' oocytes to the offspring. The contribution of genome-independent mechanisms (namely mitophagy) in this transmission were also explored. Finally, potential interventions aimed at improving oocyte/embryo health were investigated, to see if they may provide an opportunity to halter the generational effects of MD.

Keywords:  Downregulated mitophagy; Maternal obesity; Metabolic dysfunction; Milpa diet; Mitochondrial metabolic dysfunction; Mitophagy; Offspring mitochondrial dysfunction; Oocyte mitochondria; Preconceptional interventions; Traditional diet

DOI:  https://doi.org/10.1016/j.bbadis.2023.166802
bioRxiv. 2023 Jun 01. pii: 2023.05.30.542959. [Epub ahead of print]

Ultrastructural analysis reveals mitochondrial placement independent of synapse placement in fine caliber C. elegans neurons.

Danielle V Riboul, Sarah Crill, Carlos Oliva, Maria Gabriela Restifo, Reggie Joseph, Kerdes Joseph, Ken C Q Nguyen, David H Hall, Yaouen Fily, Gregory T Macleod.

Neurons rely on mitochondria for an efficient supply of ATP and other metabolites. However, while neurons are highly elongated, mitochondria are discrete and limited in number. Due to the slow rates of diffusion of long distances it follows that neurons would benefit from an ability to control the distribution of mitochondria to sites of high metabolic activity, such as synapses. It is assumed that neurons' possess this capacity, but ultrastructural data over substantial portions of a neuron's extent that would allow for tests of such hypotheses are scarce. Here, we mined the Caenorhabditis elegans' electron micrographs of John White and Sydney Brenner and found systematic differences in average mitochondrial size (ranging from 1.4 to 2.6 μm), volume density (3.8% to 7.1%) and diameter (0.19 to 0.25 μm) between neurons of different neurotransmitter type and function, but found no differences in mitochondrial morphometrics between axons and dendrites of the same neurons. Analyses of distance intervals found mitochondria to be distributed randomly with respect to both presynaptic and postsynaptic specializations. Presynaptic specializations were primarily localized to varicosities, but mitochondria were no more likely to be found in synaptic varicosities than non-synaptic varicosities. Consistently, mitochondrial volume density was no greater in varicosities with synapses. Therefore, beyond the capacity to disperse mitochondria throughout their length, at least in C. elegans , fine caliber neurons manifest little in the way of subcellular control of mitochondria.
SIGNIFICANCE: Brain function is unequivocally reliant on mitochondrial function for its energy needs, and the mechanisms that cells use to control these organelles is an active field of enquiry. WormImage, a decades old electron microscopy database in the public domain, contains information about the ultrastructural disposition of mitochondria within the nervous system over previously unexamined extents. In a largely remote format, a team of undergraduate students, coordinated by a graduate student, mined this database over the course of the pandemic. We found heterogeneity in mitochondrial size and density between, but not within, the fine caliber neurons of C. elegans . While neurons are clearly able to disperse mitochondria throughout their extent, we found little evidence that that they "install" mitochondria at synapses.

DOI: https://doi.org/10.1101/2023.05.30.542959
J Clin Invest. 2023 07 03. pii: e162479. [Epub ahead of print]133(13):

CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.

Young Jae Bahn, Hariom Yadav, Paolo Piaggi, Brent S Abel, Oksana Gavrilova, Danielle A Springer, Ioannis Papazoglou, Patricia M Zerfas, Monica C Skarulis, Alexandra C McPherron, Sushil G Rane.

  Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.

Keywords:  Metabolism; Mitochondria; Muscle Biology; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI162479
PLoS Pathog. 2023 Jul;19(7): e1011471

To eat or not to eat mitochondria? How do host cells cope with mitophagy upon bacterial infection?

Jérémy Verbeke, Xavier De Bolle, Thierry Arnould.

Mitochondria fulfil a plethora of cellular functions ranging from energy production to regulation of inflammation and cell death control. The fundamental role of mitochondria makes them a target of choice for invading pathogens, with either an intracellular or extracellular lifestyle. Indeed, the modulation of mitochondrial functions by several bacterial pathogens has been shown to be beneficial for bacterial survival inside their host. However, so far, relatively little is known about the importance of mitochondrial recycling and degradation pathways through mitophagy in the outcome (success or failure) of bacterial infection. On the one hand, mitophagy could be considered as a defensive response triggered by the host upon infection to maintain mitochondrial homeostasis. However, on the other hand, the pathogen itself may initiate the host mitophagy to escape from mitochondrial-mediated inflammation or antibacterial oxidative stress. In this review, we will discuss the diversity of various mechanisms of mitophagy in a general context, as well as what is currently known about the different bacterial pathogens that have developed strategies to manipulate the host mitophagy.

DOI: https://doi.org/10.1371/journal.ppat.1011471
Acta Pharmacol Sin. 2023 Jul 04.

Inhibition of TMEM16A improves cisplatin-induced acute kidney injury via preventing DRP1-mediated mitochondrial fission.

Xiao-Long Li, Xue-Wu Liu, Wei-Ling Liu, Yu-Quan Lin, Jing Liu, Yu-Sheng Peng, Li-Min Cheng, Yan-Hua Du.

  Acute kidney injury (AKI) is associated with high morbidity and mortality. Our previous study has demonstrated that TMEM16A, a Ca2+-activated chloride channel, contributes to renal fibrosis progression in chronic kidney disease. However, whether TMEM16A is involved in AKI is still unknown. In this study, we established cisplatin AKI mice model and found that TMEM16A expression was upregulated in the injured kidney. In vivo knockdown of TMEM16A effectively prevented cisplatin-induced tubular cell apoptosis, inflammation and kidney function loss. Western blot and transmission electron microscopy (TEM) revealed that TMEM16A knockdown inhibited Drp1 translocation from the cytoplasm to mitochondria and prevented mitochondrial fission in tubular cells. Consistently, in cultured HK2 cells, knockdown or inhibition of TMEM16A by shRNA or its specific inhibitor suppressed cisplatin-induced mitochondrial fission and its associated energy dysfunction, ROS accumulation, and cell apoptosis via inhibiting Drp1 activation. Further investigation showed that genetic knockdown or pharmacological inhibition of TMEM16A inhibited cisplatin-induced Drp1 Ser-616 site phosphorylation through ERK1/2 signaling pathway, whereas overexpression of TMEM16A promoted this effect. Treatment with Drp1 or ERK1/2 inhibitor could efficiently prevent cisplatin-induced mitochondrial fission. Collectively, our data suggest that TMEM16A inhibition alleviated cisplatin-induced AKI by preventing tubular cell mitochondrial fission through the ERK1/2 / Drp1 pathway. Inhibition of TMEM16A may be a novel therapeutic strategy for AKI.

Keywords:  AKI; Drp1; TMEM16A; cell apoptosis; mitochondrial fission

DOI:  https://doi.org/10.1038/s41401-023-01122-6
iScience. 2023 Jul 21. 26(7): 107136

Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.

Shixuan Zhang, Junrou Zhang, Luli Wu, Li Chen, Piye Niu, Jie Li.

  Excessive exposure to manganese (Mn) can cause neurological abnormalities, but the mechanism of Mn neurotoxicity remains unclear. Previous studies have shown that abnormal mitochondrial metabolism is a crucial mechanism underlying Mn neurotoxicity. Therefore, improving neurometabolic in neuronal mitochondria may be a potential therapy for Mn neurotoxicity. Here, single-cell sequencing revealed that Mn affected mitochondrial neurometabolic pathways and unfolded protein response in zebrafish dopaminergic neurons. Metabolomic analysis indicated that Mn inhibited the glutathione metabolic pathway in human neuroblastoma (SH-SY5Y) cells. Mechanistically, Mn exposure inhibited glutathione (GSH) and mitochondrial unfolded protein response (UPRmt). Furthermore, supplementation with glutamine (Gln) can effectively increase the concentration of GSH and triggered UPRmt which can alleviate mitochondrial dysfunction and counteract the neurotoxicity of Mn. Our findings highlight that UPRmt is involved in Mn-induced neurotoxicity and glutathione metabolic pathway affects UPRmt to reverse Mn neurotoxicity. In addition, Gln supplementation may have potential therapeutic benefits for Mn-related neurological disorders.

Keywords:  Biochemistry; Cell biology; Metabolomics; Toxicology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.107136
Front Endocrinol (Lausanne). 2023 ;14 1132342

Mitochondria-associated regulation in adipose tissues and potential reagents for obesity intervention.

Yali Zheng, Ni Yang, Yueshan Pang, Yanju Gong, Hong Yang, Weijun Ding, Hongya Yang.

   Introduction: A systematic review analysis was used to assess the profile of mitochondrial involvement in adipose tissue regulation and potential reagents to intervene in obesity through the mitochondrial pathway.
Methods: Three databases, PubMed, Web of Science, and Embase, were searched online for literature associated with mitochondria, obesity, white adipose tissue, and brown adipose tissue published from the time of their creation until June 22, 2022, and each paper was screened.
Results: 568 papers were identified, of which 134 papers met the initial selection criteria, 76 were selected after full-text review, and 6 were identified after additional searches. A full-text review of the included 82 papers was performed.
Conclusion: Mitochondria play a key role in adipose tissue metabolism and energy homeostasis, including as potential therapeutic agents for obesity.

Keywords:  UCP1; brown adipose tissue (BAT); mitochondria; obesity; white adipose tissue (WAT)

DOI:  https://doi.org/10.3389/fendo.2023.1132342
Nat Cell Biol. 2023 Jul 03.

Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis.

Ludovic Enkler, Viktoria Szentgyörgyi, Mirjam Pennauer, Cristina Prescianotto-Baschong, Isabelle Riezman, Aneta Wiesyk, Reut Ester Avraham, Martin Spiess, Einat Zalckvar, Roza Kucharczyk, Howard Riezman, Anne Spang.

Lipid mobilization through fatty acid β-oxidation is a central process essential for energy production during nutrient shortage. In yeast, this catabolic process starts in the peroxisome from where β-oxidation products enter mitochondria and fuel the tricarboxylic acid cycle. Little is known about the physical and metabolic cooperation between these organelles. Here we found that expression of fatty acid transporters and of the rate-limiting enzyme involved in β-oxidation is decreased in cells expressing a hyperactive mutant of the small GTPase Arf1, leading to an accumulation of fatty acids in lipid droplets. Consequently, mitochondria became fragmented and ATP synthesis decreased. Genetic and pharmacological depletion of fatty acids phenocopied the arf1 mutant mitochondrial phenotype. Although β-oxidation occurs in both mitochondria and peroxisomes in mammals, Arf1's role in fatty acid metabolism is conserved. Together, our results indicate that Arf1 integrates metabolism into energy production by regulating fatty acid storage and utilization, and presumably organelle contact sites.

DOI: https://doi.org/10.1038/s41556-023-01180-2
bioRxiv. 2023 May 29. pii: 2023.05.29.542732. [Epub ahead of print]

The variable domain from the mitochondrial fission mechanoenzyme Drp1 promotes liquid-liquid phase separation.

Ammon E Posey, Mehran Bagheri, Kyle A Ross, Elizabeth N Lanum, Misha A Khan, Christine M Jennings, Megan C Harwig, Nolan W Kennedy, Vincent J Hilser, James L Harden, R Blake Hill.

Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a "variable domain" (VD) important for regulation. For the mitochondrial fission dynamin, Drp1, a regulatory role for the VD is demonstrated by mutations that can elongate, or fragment, mitochondria. How the VD encodes inhibitory and stimulatory activity is unclear. Here, isolated VD is shown to be intrinsically disordered (ID) yet undergoes a cooperative transition in the stabilizing osmolyte TMAO. However, the TMAO stabilized state is not folded and surprisingly appears as a condensed state. Other co-solutes including known molecular crowder Ficoll PM 70, also induce a condensed state. Fluorescence recovery after photobleaching experiments reveal this state to be liquid-like indicating the VD undergoes a liquid-liquid phase separation under crowding conditions. These crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid, raising the possibility that phase separation may enable rapid tuning of Drp1 assembly necessary for fission.

DOI: https://doi.org/10.1101/2023.05.29.542732
Front Mol Neurosci. 2023 ;16 1196504

A new microfluidic model to study dendritic remodeling and mitochondrial dynamics during axonal regeneration of adult zebrafish retinal neurons.

Annelies Van Dyck, Luca Masin, Steven Bergmans, Giel Schevenels, An Beckers, Benoit Vanhollebeke, Lieve Moons.

  Unlike mammals, adult zebrafish are able to fully regenerate axons and functionally recover from neuronal damage in the mature central nervous system (CNS). Decades of research have tried to identify the mechanisms behind their spontaneous regenerative capacity, but the exact underlying pathways and molecular drivers remain to be fully elucidated. By studying optic nerve injury-induced axonal regrowth of adult zebrafish retinal ganglion cells (RGCs), we previously reported transient dendritic shrinkage and changes in the distribution and morphology of mitochondria in the different neuronal compartments throughout the regenerative process. These data suggest that dendrite remodeling and temporary changes in mitochondrial dynamics contribute to effective axonal and dendritic repair upon optic nerve injury. To further elucidate these interactions, we here present a novel adult zebrafish microfluidic model in which we can demonstrate compartment-specific alterations in resource allocation in real-time at single neuron level. First, we developed a pioneering method that enables to isolate and culture adult zebrafish retinal neurons in a microfluidic setup. Notably, with this protocol, we report on a long-term adult primary neuronal culture with a high number of surviving and spontaneously outgrowing mature neurons, which was thus far only very limitedly described in literature. By performing time-lapse live cell imaging and kymographic analyses in this setup, we can explore changes in dendritic remodeling and mitochondrial motility during spontaneous axonal regeneration. This innovative model system will enable to discover how redirecting intraneuronal energy resources supports successful regeneration in the adult zebrafish CNS, and might facilitate the discovery of new therapeutic targets to promote neuronal repair in humans.

Keywords:  axonal regeneration; dendrites; in vitro; microfluidics; mitochondria; zebrafish

DOI:  https://doi.org/10.3389/fnmol.2023.1196504
J Transl Med. 2023 Jul 05. 21(1): 441

Mitochondria in endothelial cells angiogenesis and function: current understanding and future perspectives.

Zhen Luo, Jianbo Yao, Zhe Wang, Jianxiong Xu.

  Endothelial cells (ECs) angiogenesis is the process of sprouting new vessels from the existing ones, playing critical roles in physiological and pathological processes such as wound healing, placentation, ischemia/reperfusion, cardiovascular diseases and cancer metastasis. Although mitochondria are not the major sites of energy source in ECs, they function as important biosynthetic and signaling hubs to regulate ECs metabolism and adaptations to local environment, thus affecting ECs migration, proliferation and angiogenic process. The understanding of the importance and potential mechanisms of mitochondria in regulating ECs metabolism, function and the process of angiogenesis has developed in the past decades. Thus, in this review, we discuss the current understanding of mitochondrial proteins and signaling molecules in ECs metabolism, function and angiogeneic signaling, to provide new and therapeutic targets for treatment of diverse cardiovascular and angiogenesis-dependent diseases.

Keywords:  Angiogenesis; Cardiovascular diseases; Endothelial cells; Mitochondrial protein; Signaling pathways

DOI:  https://doi.org/10.1186/s12967-023-04286-1
Chempluschem. 2023 Jul 03. e202300203

Photo-Lipids: Light-Sensitive Nano-Switches To Control Membrane Properties.

Larissa Socrier, Claudia Steinem.

  Biological membranes are described as a complex mixture of lipids and proteins organized according to thermodynamic principles. This chemical and spatial complexity can lead to specialized functional membrane domains enriched with specific lipids and proteins. The interaction between lipids and proteins restricts their lateral diffusion and range of motion, thus altering their function. One approach to investigating these membrane properties is to use chemically accessible probes. In particular, photo-lipids, which contain a light-sensitive azobenzene moiety that changes its configuration from trans- to cis- upon light irradiation, have recently gained popularity for modifying membrane properties. These azobenzene-derived lipids serve as nanotools for manipulating lipid membranes in vitro and in vivo. Here, we will discuss the use of these compounds in artificial and biological membranes as well as their application in drug delivery. We will focus mainly on changes in the membrane's physical properties as well as lipid membrane domains in phase-separated liquid-ordered/liquid-disordered bilayers driven by light, and how these changes in membrane physical properties alter transmembrane protein function.

Keywords:  Azobenzene * light * membrane * photoswitchable lipids * photo-pharmacology

DOI:  https://doi.org/10.1002/cplu.202300203
iScience. 2023 Jul 21. 26(7): 107113

Restoration of mitochondrial function by Spirulina polysaccharide via upregulated SOD2 in aging fibroblasts.

Kayo Machihara, Shoma Oki, Yuka Maejima, Sou Kageyama, Ayumu Onda, Yurino Koseki, Yasuyuki Imai, Takushi Namba.

  Reactive oxygen species (ROS), such as superoxide, are crucial factors involved in the stimulation of cellular aging. Mitochondria, which are important organelles responsible for various metabolic processes in cells, produce ROS. These ROS impair mitochondrial function, thereby accelerating aging-related cellular dysfunction. Herein, we demonstrated that the Spirulina polysaccharide complex (SPC) restores mitochondrial function and collagen production by scavenging superoxide via the upregulation of superoxide dismutase 2 (SOD2) in aging fibroblasts. We observed that SOD2 expression was linked to inflammatory pathways; however, SPC did not upregulate the expression of most inflammatory cytokines produced as a result of induction of LPS in aging fibroblasts, indicating that SPC induces SOD2 without activation of inflammatory pathways. Furthermore, SPC stimulated endoplasmic reticulum (ER) protein folding by upregulating ER chaperones expression. Thus, SPC is proposed to be an antiaging material that rejuvenates aging fibroblasts by increasing their antioxidant potential via the upregulation of SOD2.

Keywords:  Cell biology; Cellular physiology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2023.107113
Nat Commun. 2023 Jul 06. 14(1): 3981

Multicomponent regulation of actin barbed end assembly by twinfilin, formin and capping protein.

Heidi Ulrichs, Ignas Gaska, Shashank Shekhar.

Cells control actin assembly by regulating reactions at actin filament barbed ends. Formins accelerate elongation, capping protein (CP) arrests growth and twinfilin promotes depolymerization at barbed ends. How these distinct activities get integrated within a shared cytoplasm is unclear. Using microfluidics-assisted TIRF microscopy, we find that formin, CP and twinfilin can simultaneously bind filament barbed ends. Three‑color, single-molecule experiments reveal that twinfilin cannot bind barbed ends occupied by formin unless CP is present. This trimeric complex is short-lived (~1 s), and results in dissociation of CP by twinfilin, promoting formin-based elongation. Thus, the depolymerase twinfilin acts as a pro-formin pro-polymerization factor when both CP and formin are present. While one twinfilin binding event is sufficient to displace CP from the barbed-end trimeric complex, ~31 twinfilin binding events are required to remove CP from a CP-capped barbed end. Our findings establish a paradigm where polymerases, depolymerases and cappers together tune actin assembly.

DOI: https://doi.org/10.1038/s41467-023-39655-3
iScience. 2023 Jul 21. 26(7): 107014

Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target.

Ira Buntenbroich, Vincent Anton, Daniel Perez-Hernandez, Tânia Simões, Felix Gaedke, Astrid Schauss, Gunnar Dittmar, Jan Riemer, Mafalda Escobar-Henriques.

  Defects in mitochondrial fusion are at the base of many diseases. Mitofusins power membrane-remodeling events via self-interaction and GTP hydrolysis. However, how exactly mitofusins mediate fusion of the outer membrane is still unclear. Structural studies enable tailored design of mitofusin variants, providing valuable tools to dissect this stepwise process. Here, we found that the two cysteines conserved between yeast and mammals are required for mitochondrial fusion, revealing two novel steps of the fusion cycle. C381 is dominantly required for the formation of the trans-tethering complex, before GTP hydrolysis. C805 allows stabilizing the Fzo1 protein and the trans-tethering complex, just prior to membrane fusion. Moreover, proteasomal inhibition rescued Fzo1 C805S levels and membrane fusion, suggesting a possible application for clinically approved drugs. Together, our study provides insights into how assembly or stability defects in mitofusins might cause mitofusin-associated diseases and uncovers potential therapeutic intervention by proteasomal inhibition.

Keywords:  Biological sciences; Cell biology; Genetics; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107014
Transl Res. 2023 Jul 05. pii: S1931-5244(23)00108-1. [Epub ahead of print]

Depleted Hexokinase1 and lack of AMPKα activation favor OXPHOS-dependent energetics in Retinoblastoma tumors.

Vishnu Suresh Babu, Ashwin Mallipatna, Gagan Dudeja, Rohit Shetty, Archana Padmanabhan Nair, Sai Bo Bo Tun, Candice Ee Hua Ho, Shyam S Chaurasia, Shomi S Bhattacharya, Navin Kumar Verma, Rajamani Lakshminarayanan, Nilanjan Guha, Stephane Heymans, Veluchamy Amutha Barathi, Arkasubhra Ghosh.

  Lack of retinoblastoma protein (Rb) causes aggressive intraocular retinal tumors in children. Recently, Rb tumors have been shown to have a distinctly altered metabolic phenotype, such as reduced expression of glycolytic pathway proteins alongside altered pyruvate and fatty acid levels. In this study, we demonstrate that loss of Hexokinase 1(HK1) in tumor cells rewires their metabolism allowing enhanced oxidative phosphorylation-dependent energy production. We show that rescuing HK1 or RB1 in these retinoblastoma cells reduced cancer hallmarks such as proliferation, invasion, spheroid formation and increased their sensitivity to chemotherapy drugs. Induction of HK1 was accompanied by a metabolic shift of the cells to glycolysis and a reduction in mitochondrial mass. Cytoplasmic HK1 bound Liver Kinase B1 (LKB1) and phosphorylated AMP-activated kinase-α (AMPKα Thr172), thereby reducing mitochondria-dependent energy production. We validated these findings in tumor samples from Rb patients compared to age-matched healthy retinae. HK1 or RB1 expression in Rb-/- cells led to a reduction in their respiratory capacity and glycolytic proton flux. HK1 overexpression reduced tumor burden in an intraocular tumor xenograft model. AMPKα activation by AICAR also enhanced the tumoricidal effects of the chemotherapeutic drug topotecan in vivo. Therefore, enhancing HK1 or AMPKα activity can reprogram cancer metabolism and sensitize retinoblastoma tumors to lower doses of existing treatments, a potential therapeutic modality for retinoblastoma.

Keywords:  AMPKα; Hexokinase-1; Retinoblastoma; cancer; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.trsl.2023.07.001