bims-mitmed 2024-02-11 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024‒02‒11
thirty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight.
The role of mitochondrial dynamics in oocyte and early embryo development.
Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.
Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.
Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.
Navigating the landscape of mitochondrial-ER communication in health and disease.
Mitochondrial DNA instability in Huntington disease.
AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.
Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).
Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.
mtDNA extramitochondrial replication mediates mitochondrial defect effects.
Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.
Shaping the Neurovascular Unit Exploiting Human Brain Organoids.
Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus.
The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.
Mitochondrial stress: a key role of neuroinflammation in stroke.
Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.
A novel mutation in the LRSAM1 gene in a family with early onset autosomal dominant Charcot-Marie-Tooth type 2P.
Teaching Video NeuroImage: TWNK Mutation Causes Chronic Progressive External Ophthalmoplegia and Cerebellar Ataxia: A POLG-Like Phenotype.
Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.
Hypermetabolism and energetic constraints in mitochondrial disorders.
Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
Efficient prime editing in two-cell mouse embryos using PEmbryo.
The New Frontiers of Gene Therapy and Gene Editing in Inflammatory Diseases.
NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model.

Nat Commun. 2024 Feb 09. 15(1): 1232

Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight.

Joke Mertens, Florence Belva, Aafke P A van Montfoort, Marius Regin, Filippo Zambelli, Sara Seneca, Edouard Couvreu de Deckersberg, Maryse Bonduelle, Herman Tournaye, Katrien Stouffs, Kurt Barbé, Hubert J M Smeets, Hilde Van de Velde, Karen Sermon, Christophe Blockeel, Claudia Spits.

Children conceived through assisted reproductive technologies (ART) have an elevated risk of lower birthweight, yet the underlying cause remains unclear. Our study explores mitochondrial DNA (mtDNA) variants as contributors to birthweight differences by impacting mitochondrial function during prenatal development. We deep-sequenced the mtDNA of 451 ART and spontaneously conceived (SC) individuals, 157 mother-child pairs and 113 individual oocytes from either natural menstrual cycles or after ovarian stimulation (OS) and find that ART individuals carried a different mtDNA genotype than SC individuals, with more de novo non-synonymous variants. These variants, along with rRNA variants, correlate with lower birthweight percentiles, independent of conception mode. Their higher occurrence in ART individuals stems from de novo mutagenesis associated with maternal aging and OS-induced oocyte cohort size. Future research will establish the long-term health consequences of these changes and how these findings will impact the clinical practice and patient counselling in the future.

DOI: https://doi.org/10.1038/s41467-024-45446-1
Semin Cell Dev Biol. 2024 Feb 06. pii: S1084-9521(24)00019-3. [Epub ahead of print]159-160 52-61

The role of mitochondrial dynamics in oocyte and early embryo development.

Raziye Melike Yildirim, Emre Seli.

  Mitochondrial dysfunction is widely implicated in various human diseases, through mechanisms that go beyond mitochondria's well-established role in energy generation. These dynamic organelles exert vital control over numerous cellular processes, including calcium regulation, phospholipid synthesis, innate immunity, and apoptosis. While mitochondria's importance is acknowledged in all cell types, research has revealed the exceptionally dynamic nature of the mitochondrial network in oocytes and embryos, finely tuned to meet unique needs during gamete and pre-implantation embryo development. Within oocytes, both the quantity and morphology of mitochondria can significantly change during maturation and post-fertilization. These changes are orchestrated by fusion and fission processes (collectively known as mitochondrial dynamics), crucial for energy production, content exchange, and quality control as mitochondria adjust to the shifting energy demands of oocytes and embryos. The roles of proteins that regulate mitochondrial dynamics in reproductive processes have been primarily elucidated through targeted deletion studies in animal models. Notably, impaired mitochondrial dynamics have been linked to female reproductive health, affecting oocyte quality, fertilization, and embryo development. Dysfunctional mitochondria can lead to fertility problems and can have an impact on the success of pregnancy, particularly in older reproductive age women.

Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; MtDNA

DOI:  https://doi.org/10.1016/j.semcdb.2024.01.007
Int J Mol Sci. 2024 Jan 23. pii: 1386. [Epub ahead of print]25(3):

Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.

Martine Uittenbogaard, Andrea L Gropman, Matthew T Whitehead, Christine A Brantner, Eliana Gropman, Anne Chiaramello.

  We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband's low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology. The proband's genotype-phenotype correlation remained undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provided evidence of a deficient oxidative-phosphorylation pathway responsible for adenosine triphosphate (ATP) synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis revealed metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirmed the suspected mitochondrial etiology, as the proband's mitochondria exhibited an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that suboptimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward oxidative phosphorylation (OXPHOS) leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of the fetal and postnatal brain.

Keywords:  OXPHOS deficit; fetal growth restriction; metabolic reprogramming; mitochondrial dysfunction; neurodevelopmental deficits; placental insufficiency

DOI:  https://doi.org/10.3390/ijms25031386
iScience. 2024 Feb 16. 27(2): 108883

Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.

Yunfan He, Gao Zhu, Xincheng Li, Mi Zhou, Min-Xin Guan.

  Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we demonstrated that mt-tRNAMet 4435A>G mutation-induced nucleotide modification deficiency dysregulated the expression of nuclear genes involved in cytosolic proteins involved in oxidative phosphorylation system (OXPHOS) and impaired the assemble and integrity of OXPHOS complexes. These dysfunctions caused mitochondrial dynamic imbalance, thereby increasing fission and decreasing fusion. Excessive fission impaired the process of autophagy including initiation phase, formation, and maturation of autophagosome. Strikingly, the m.4435A>G mutation upregulated the PARKIN dependent mitophagy pathways but downregulated the ubiquitination-independent mitophagy. These alterations promoted intrinsic apoptotic process for the removal of damaged cells. Our findings provide new insights into mechanism underlying deficient tRNA posttranscription modification regulated intracellular signaling related to the mitochondrial and cellular integrity.

Keywords:  Cell biology; Molecular physiology; Properties of biomolecules

DOI:  https://doi.org/10.1016/j.isci.2024.108883
Hum Mol Genet. 2024 Feb 07. pii: ddae018. [Epub ahead of print]

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.

Vanitha Nithianandam, Souvarish Sarkar, Mel B Feany.

  Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.

Keywords:  Drosophila; complex I deficiency; mitochondria; neurotoxicity; proteostasis

DOI:  https://doi.org/10.1093/hmg/ddae018
Front Endocrinol (Lausanne). 2023 ;14 1346441

Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.

Ruijing Chen, Jun Chen.

  Metabolic disorders remain a major global health concern in the 21st century, with increasing incidence and prevalence. Mitochondria play a critical role in cellular energy production, calcium homeostasis, signal transduction, and apoptosis. Under physiological conditions, mitochondrial transfer plays a crucial role in tissue homeostasis and development. Mitochondrial dysfunction has been implicated in the pathogenesis of metabolic disorders. Numerous studies have demonstrated that mitochondria can be transferred from stem cells to pathologically injured cells, leading to mitochondrial functional restoration. Compared to cell therapy, mitochondrial transplantation has lower immunogenicity, making exogenous transplantation of healthy mitochondria a promising therapeutic approach for treating diseases, particularly metabolic disorders. This review summarizes the association between metabolic disorders and mitochondria, the mechanisms of mitochondrial transfer, and the therapeutic potential of mitochondrial transfer for metabolic disorders. We hope this review provides novel insights into targeted mitochondrial therapy for metabolic disorders.

Keywords:  metabolic diseases; mitochondria; mitochondrial transfer; therapy; transplantation

DOI:  https://doi.org/10.3389/fendo.2023.1346441
Front Mol Biosci. 2024 ;11 1356500

Navigating the landscape of mitochondrial-ER communication in health and disease.

Conor T Ronayne, Pedro Latorre-Muro.

  Intracellular organelle communication enables the maintenance of tissue homeostasis and health through synchronized adaptive processes triggered by environmental cues. Mitochondrial-Endoplasmic Reticulum (ER) communication sustains cellular fitness by adjusting protein synthesis and degradation, and metabolite and protein trafficking through organelle membranes. Mitochondrial-ER communication is bidirectional and requires that the ER-components of the Integrated Stress Response signal to mitochondria upon activation and, likewise, mitochondria signal to the ER under conditions of metabolite and protein overload to maintain proper functionality and ensure cellular survival. Declines in the mitochondrial-ER communication occur upon ageing and correlate with the onset of a myriad of heterogeneous age-related diseases such as obesity, type 2 diabetes, cancer, or neurodegenerative pathologies. Thus, the exploration of the molecular mechanisms of mitochondrial-ER signaling and regulation will provide insights into the most fundamental cellular adaptive processes with important therapeutical opportunities. In this review, we will discuss the pathways and mechanisms of mitochondrial-ER communication at the mitochondrial-ER interface and their implications in health and disease.

Keywords:  calcium signaling; cellular fitness; endoplasmic reticulum; lipid trafficking; mitochondria; mitochondrial-ER communication; protein homeostasis; unfolded protein response

DOI:  https://doi.org/10.3389/fmolb.2024.1356500
Nat Rev Neurol. 2024 Feb 07.

Mitochondrial DNA instability in Huntington disease.

Lisa Kiani.

DOI: https://doi.org/10.1038/s41582-024-00937-z
Sci Adv. 2024 Feb 09. 10(6): eadj2752

AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.

Liwei Xiao, Yujing Yin, Zongchao Sun, Jing Liu, Yuhuan Jia, Likun Yang, Yan Mao, Shujun Peng, Zhifu Xie, Lei Fang, Jingya Li, Xiaoduo Xie, Zhenji Gan.

Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.

DOI: https://doi.org/10.1126/sciadv.adj2752
Nat Commun. 2024 Feb 06. 15(1): 1124

Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.

Aidan Anderson, Nada Alfahad, Dulani Wimalachandra, Kaouthar Bouzinab, Paula Rudzinska, Heather Wood, Isabel Fazey, Heping Xu, Timothy J Lyons, Nicholas M Barnes, Parth Narendran, Janet M Lord, Saaeha Rauz, Ian G Ganley, Tim M Curtis, Graham R Wallace, Jose R Hombrebueno.

The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.

DOI: https://doi.org/10.1038/s41467-024-45387-9
Cells. 2024 Jan 29. pii: 248. [Epub ahead of print]13(3):

Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.

Teresa Cunha-Oliveira, Liliana Montezinho, Rui F Simões, Marcelo Carvalho, Elisabete Ferreiro, Filomena S G Silva.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease.

Keywords:  amyotrophic lateral sclerosis; mitochondria-targeted therapies; mitochondrial dysfunction; motor neuron degeneration; neurodegeneration; pathological mechanisms; therapeutic interventions

DOI:  https://doi.org/10.3390/cells13030248
J Pharm Sci. 2024 Feb 05. pii: S0022-3549(24)00041-8. [Epub ahead of print]

Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).

Itsumi Sato, Mitsue Hibino, Atsuhito Takeda, Hideyoshi Harashima, Yuma Yamada.

  Numerous mitochondria are present in skeletal muscle cells. Muscle disease and aging impair mitochondrial functioning in the skeletal muscle. However, there have been few reports of therapeutic intervention via drug delivery to mitochondria owing to methodological difficulties. We surmised that mitochondrial activation is associated with improved skeletal muscle function. In this study, we attempted to activate the mitochondrial respiratory capacity in rat skeletal muscle cells (L6 cells) by delivering Coenzyme Q10 (CoQ10), a mitochondrial functional activator, to mitochondria using MITO-Porter, a nanoparticle that facilitates mitochondria-targeted drug delivery. Cellular uptake was confirmed by measuring the amount of fluorescence-modified MITO-Porter taken up by cells using flow cytometry. Intracellular dynamics of MITO-Porter was observed using confocal laser scanning microscopy. Mitochondrial function was assessed by measuring the mitochondrial oxygen consumption rate using an extracellular flux analyzer. The results indicated MITO-Porter-assisted delivery of CoQ10 to the mitochondria activated mitochondrial respiratory capacity in L6 cells. We believe that our results indicate the possibility of skeletal muscle therapy using mitochondrial drug delivery.

Keywords:  Drug delivery system; Lipid Nanoparticle (LNP); Liposome; Microfluidics; Muscle; Nanoparticle; Nanotechnology

DOI:  https://doi.org/10.1016/j.xphs.2024.01.020
J Cell Biol. 2024 Mar 04. pii: e202310005. [Epub ahead of print]223(3):

Regulation of proteostasis and innate immunity via mitochondria-nuclear communication.

Sookyung Kim, Theresa R Ramalho, Cole M Haynes.

Mitochondria are perhaps best known as the "powerhouse of the cell" for their role in ATP production required for numerous cellular activities. Mitochondria have emerged as an important signaling organelle. Here, we first focus on signaling pathways mediated by mitochondria-nuclear communication that promote protein homeostasis (proteostasis). We examine the mitochondrial unfolded protein response (UPRmt) in C. elegans, which is regulated by a transcription factor harboring both a mitochondrial- and nuclear-targeting sequence, the integrated stress response in mammals, as well as the regulation of chromatin by mitochondrial metabolites. In the second section, we explore the role of mitochondria-to-nuclear communication in the regulation of innate immunity and inflammation. Perhaps related to their prokaryotic origin, mitochondria harbor molecules also found in viruses and bacteria. If these molecules accumulate in the cytosol, they elicit the same innate immune responses as viral or bacterial infection.

DOI: https://doi.org/10.1083/jcb.202310005
iScience. 2024 Feb 16. 27(2): 108970

mtDNA extramitochondrial replication mediates mitochondrial defect effects.

Zhaoliang Shan, Shengnan Li, Yuxue Gao, Chunhua Jian, Xiuxiu Ti, Hui Zuo, Ying Wang, Guochun Zhao, Yan Wang, Qing Zhang.

  A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases.

Keywords:  Biological sciences; Molecular biology; Molecular genetics; Molecular interaction

DOI:  https://doi.org/10.1016/j.isci.2024.108970
FEBS Lett. 2024 Feb 04.

Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.

Aksel J Saukko-Paavola, Robin W Klemm.

  Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.

Keywords:  autophagy; endoplasmic reticulum (ER); lipid droplets (LDs); membrane contact sites; metabolic adaptation; mitochondria; mitochondrial shape; organelle-network; starvation

DOI:  https://doi.org/10.1002/1873-3468.14813
Sci Signal. 2024 Feb 06. 17(822): eabq1007

A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.

Ismael Izquierdo-Villalba, Serena Mirra, Yasmina Manso, Antoni Parcerisas, Javier Rubio, Jaume Del Valle, Francisco J Gil-Bea, Fausto Ulloa, Marina Herrero-Lorenzo, Ester Verdaguer, Cristiane Benincá, Rubén D Castro-Torres, Elena Rebollo, Gemma Marfany, Carme Auladell, Xavier Navarro, José A Enríquez, Adolfo López de Munain, Eduardo Soriano, Anna M Aragay.

Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein-coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gαq inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat-containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.

DOI: https://doi.org/10.1126/scisignal.abq1007
Mol Neurobiol. 2024 Feb 09.

Shaping the Neurovascular Unit Exploiting Human Brain Organoids.

Mafalda Rizzuti, Valentina Melzi, Lorenzo Brambilla, Lorenzo Quetti, Luca Sali, Linda Ottoboni, Megi Meneri, Antonia Ratti, Federico Verde, Nicola Ticozzi, Giacomo Pietro Comi, Stefania Corti, Elena Abati.

  Brain organoids, three-dimensional cell structures derived from pluripotent stem cells, closely mimic key aspects of the human brain in vitro, providing a powerful tool for studying neurodevelopment and disease. The neuroectodermal induction protocol employed for brain organoid generation primarily gives rise to the neural cellular component but lacks the vital vascular system, which is crucial for the brain functions by regulating differentiation, migration, and circuit formation, as well as delivering oxygen and nutrients. Many neurological diseases are caused by dysfunctions of cerebral microcirculation, making vascularization of human brain organoids an important tool for pathogenetic and translational research. Experimentally, the creation of vascularized brain organoids has primarily focused on the fusion of vascular and brain organoids, on organoid transplantation in vivo, and on the use of microfluidic devices to replicate the intricate microenvironment of the human brain in vitro. This review summarizes these efforts and highlights the importance of studying the neurovascular unit in a forward-looking perspective of leveraging their use for understanding and treating neurological disorders.

Keywords:  Cerebral organoids; Circulation; Microcirculation; Pluripotent stem cells; Vascular organoids; Vascular system

DOI:  https://doi.org/10.1007/s12035-024-03998-9
Int J Mol Sci. 2024 Feb 05. pii: 1912. [Epub ahead of print]25(3):

Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus.

Davide Doni, Eva Cavallari, Martin Ezequiel Noguera, Hernan Gustavo Gentili, Federica Cavion, Gustavo Parisi, Maria Silvina Fornasari, Geppo Sartori, Javier Santos, Massimo Bellanda, Donatella Carbonera, Paola Costantini, Marco Bortolus.

  Nqo15 is a subunit of respiratory complex I of the bacterium Thermus thermophilus, with strong structural similarity to human frataxin (FXN), a protein involved in the mitochondrial disease Friedreich's ataxia (FRDA). Recently, we showed that the expression of recombinant Nqo15 can ameliorate the respiratory phenotype of FRDA patients' cells, and this prompted us to further characterize both the Nqo15 solution's behavior and its potential functional overlap with FXN, using a combination of in silico and in vitro techniques. We studied the analogy of Nqo15 and FXN by performing extensive database searches based on sequence and structure. Nqo15's folding and flexibility were investigated by combining nuclear magnetic resonance (NMR), circular dichroism, and coarse-grained molecular dynamics simulations. Nqo15's iron-binding properties were studied using NMR, fluorescence, and specific assays and its desulfurase activation by biochemical assays. We found that the recombinant Nqo15 isolated from complex I is monomeric, stable, folded in solution, and highly dynamic. Nqo15 does not share the iron-binding properties of FXN or its desulfurase activation function.

Keywords:  Frataxin; Friedreich’s ataxia; Nqo15

DOI:  https://doi.org/10.3390/ijms25031912
Cell Mol Life Sci. 2024 Feb 09. 81(1): 80

The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.

Corentin Affortit, Carolanne Coyat, Anissa Rym Saidia, Jean-Charles Ceccato, Majida Charif, Emmanuelle Sarzi, Frédéric Flamant, Romain Guyot, Chantal Cazevieille, Jean-Luc Puel, Guy Lenaers, Jing Wang.

  Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

Keywords:  Deafness; Hereditary optic neuropathy; Hidden hearing loss; Inner ear; Inner hair cell; Mitochondrial homeostasis; Outer hair cell; Retina

DOI:  https://doi.org/10.1007/s00018-024-05115-4
J Neuroinflammation. 2024 Feb 06. 21(1): 44

Mitochondrial stress: a key role of neuroinflammation in stroke.

Ling Gao, Li Peng, Jian Wang, John H Zhang, Ying Xia.

  Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused by the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as a pivotal event contributing to neuronal cell death. The occurrence and progression of neuroinflammation entail intricate processes, prominently featuring mitochondrial dysfunction and adaptive responses. Mitochondria, a double membrane-bound organelle are recognized as the "energy workshop" of the body. Brain is particularly vulnerable to mitochondrial disturbances due to its high energy demands from mitochondria-related energy production. The interplay between mitochondria and neuroinflammation plays a significant role in the pathogenesis of stroke. The biological and pathological consequences resulting from mitochondrial stress have substantial implications for cerebral function. Mitochondrial stress serves as an adaptive mechanism aimed at mitigating the stress induced by the import of misfolded proteins, which occurs in response to stroke. This adaptive response involves a reduction in misfolded protein accumulation and overall protein synthesis. The influence of mitochondrial stress on the pathological state of stroke is underscored by its capacity to interact with neuroinflammation. The impact of mitochondrial stress on neuroinflammation varies according to its severity. Moderate mitochondrial stress can bolster cellular adaptive defenses, enabling cells to better withstand detrimental stressors. In contrast, sustained and excessive mitochondrial stress detrimentally affects cellular and tissue integrity. The relationship between neuroinflammation and mitochondrial stress depends on the degree of mitochondrial stress present. Understanding its role in stroke pathogenesis is instrumental in excavating the novel treatment of stroke. This review aims to provide the evaluation of the cross-talk between mitochondrial stress and neuroinflammation within the context of stroke. We aim to reveal how mitochondrial stress affects neuroinflammation environment in stroke.

Keywords:  Mitochondrial stress; Mitophagy; Neuroinflammation; Stroke

DOI:  https://doi.org/10.1186/s12974-024-03033-7
Nat Cell Biol. 2024 Feb 08.

Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.

Laura E Newman, Sammy Weiser Novak, Gladys R Rojas, Nimesha Tadepalle, Cara R Schiavon, Danielle A Grotjahn, Christina G Towers, Marie-Ève Tremblay, Matthew P Donnelly, Sagnika Ghosh, Michaela Medina, Sienna Rocha, Ricardo Rodriguez-Enriquez, Joshua A Chevez, Ian Lemersal, Uri Manor, Gerald S Shadel.

Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.

DOI: https://doi.org/10.1038/s41556-023-01343-1
Cell Metab. 2024 Jan 30. pii: S1550-4131(24)00008-1. [Epub ahead of print]

Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells.

Theresa Ramalho, Patricia A Assis, Ogooluwa Ojelabi, Lin Tan, Brener Carvalho, Luiz Gardinassi, Osvaldo Campos, Philip L Lorenzi, Katherine A Fitzgerald, Cole Haynes, Douglas T Golenbock, Ricardo T Gazzinelli.

  Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.

Keywords:  PD-1; PD-L1; Plasmodium chabaudi; TCA cycle; cGAS-STING; immuno checkpoint markers; inate immunity; itaconate; itaconic acid; lymphocytes; malaria; metabolism; methylenesuccinic acid; mitochondria; mitochondrial DNA; monocyte-derived dendritic cells; mtDNA

DOI:  https://doi.org/10.1016/j.cmet.2024.01.008
Clin Neurol Neurosurg. 2024 Feb 03. pii: S0303-8467(24)00045-3. [Epub ahead of print]237 108158

A novel mutation in the LRSAM1 gene in a family with early onset autosomal dominant Charcot-Marie-Tooth type 2P.

Giammarco Milella, Alessandro Amati, Patrizia Lastella, Paola Zanfardino, Vittoria Petruzzella, Stefano Zoccolella.

  Charcot-Marie-Tooth disease type 2P (CMT2P; MIM #614436) is a specific type of axonal neuropathy caused by mutations in the LRSAM1 gene, which is a RING-type E3 ubiquitin ligase. CMT2P can be inherited in two ways: as an autosomal dominant or autosomal recessive trait. In this report, we describe the clinical characteristics of a family with axonal sensory-motor neuropathy caused by a new variant of the LSRAM1 gene, which is associated with early-onset autosomal dominant CMT2P.

Keywords:  Axonal sensory-motor polyneuropathy; Charcot-Marie-Tooth disease type 2P; Dominant inheritance; Heterozygous variant; LRSAM1 gene

DOI:  https://doi.org/10.1016/j.clineuro.2024.108158
Neurology. 2024 Mar 12. 102(5): e209186

Teaching Video NeuroImage: TWNK Mutation Causes Chronic Progressive External Ophthalmoplegia and Cerebellar Ataxia: A POLG-Like Phenotype.

Pedro H A Fraiman, Thiago Y T Silva, José Luiz Pedroso, Orlando G P Barsottini.

DOI: https://doi.org/10.1212/WNL.0000000000209186
EMBO J. 2024 Feb 09.

Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.

Esmee Vringer, Rosalie Heilig, Joel S Riley, Annabel Black, Catherine Cloix, George Skalka, Alfredo E Montes-Gómez, Aurore Aguado, Sergio Lilla, Henning Walczak, Mads Gyrd-Hansen, Daniel J Murphy, Danny T Huang, Sara Zanivan, Stephen Wg Tait.

  Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.

Keywords:  Cell Death; Inflammation; Mitochondria; NF-κB; Ubiquitin

DOI:  https://doi.org/10.1038/s44318-024-00044-1
Nat Metab. 2024 Feb 09.

Hypermetabolism and energetic constraints in mitochondrial disorders.

Alexander J Sercel, Gabriel Sturm, Dympna Gallagher, Marie-Pierre St-Onge, Christopher P Kempes, Herman Pontzer, Michio Hirano, Martin Picard.

DOI: https://doi.org/10.1038/s42255-023-00968-8
Neuron. 2024 Feb 07. pii: S0896-6273(24)00037-0. [Epub ahead of print]112(3): 520

Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.

Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.

DOI: https://doi.org/10.1016/j.neuron.2024.01.011
Nat Biotechnol. 2024 Feb 06.

Efficient prime editing in two-cell mouse embryos using PEmbryo.

Rebecca P Kim-Yip, Ryan McNulty, Bradley Joyce, Antonio Mollica, Peter J Chen, Purnima Ravisankar, Benjamin K Law, David R Liu, Jared E Toettcher, Evgueni A Ivakine, Eszter Posfai, Britt Adamson.

Using transient inhibition of DNA mismatch repair during a permissive stage of development, we demonstrate highly efficient prime editing of mouse embryos with few unwanted, local byproducts (average 58% precise edit frequency, 0.5% on-target error frequency across 13 substitution edits at 8 sites), enabling same-generation phenotyping of founders. Whole-genome sequencing reveals that mismatch repair inhibition increases off-target indels at low-complexity regions in the genome without any obvious phenotype in mice.

DOI: https://doi.org/10.1038/s41587-023-02106-x
Hum Gene Ther. 2024 Feb 07.

The New Frontiers of Gene Therapy and Gene Editing in Inflammatory Diseases.

Alessandro Romano, Alessandra Mortellaro.

Inflammatory diseases are conditions characterized by abnormal and often excessive immune responses, leading to tissue and organ inflammation. The complexity of these disorders arises from the intricate interplay of genetic factors and immune responses, which challenges conventional therapeutic approaches. However, the field of genetic manipulation has sparked unprecedented optimism in addressing these complex disorders. This review aims to comprehensively explore the application of gene therapy and gene editing in the context of inflammatory diseases, offering solutions that range from correcting genetic defects to precise immune modulation. These therapies have exhibited remarkable potential in ameliorating symptoms, improving quality of life, and even achieving disease remission. As we delve into recent breakthroughs and therapeutic applications, we illustrate how these advancements offer novel and transformative solutions for conditions that have traditionally eluded conventional treatments. By examining successful case studies and pre-clinical research, we emphasize the favorable results and substantial transformative impacts that gene-based interventions have demonstrated in patients and animal models of inflammatory diseases such as chronic granulomatous disease, cryopyrin-associated syndromes, and adenosine deaminase 2 deficiency, as well as those of multifactorial origins like arthropathies (osteoarthritis, rheumatoid arthritis) and inflammatory bowel disease. In conclusion, gene therapy and gene editing offer transformative opportunities to address the underlying causes of inflammatory diseases, ushering in a new era of precision medicine and providing hope for personalized, targeted treatments.

DOI: https://doi.org/10.1089/hum.2023.210
Sci Rep. 2024 02 05. 14(1): 2975

NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model.

Matthias Christen, Anne Gregor, Rodrigo Gutierrez-Quintana, Jos Bongers, Angie Rupp, Jacques Penderis, G Diane Shelton, Vidhya Jagannathan, Christiane Zweier, Tosso Leeb.

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

DOI: https://doi.org/10.1038/s41598-024-53314-7