bims-midneu 2021-07-04 papers

bims-midneu

Biomed News

on Mitochondrial dysfunction in neurodegeneration

Issue of 2021–07–04
28 papers selected by
Radha Desai, Merck Sharp & Dohme Corp.

Effect of Chronic Stress Present in Fibroblasts Derived from Patients with a Sporadic Form of AD on Mitochondrial Function and Mitochondrial Turnover.
Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia.
The PINK1-Mediated Crosstalk between Neural Cells and the Underlying Link to Parkinson's Disease.
The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication.
Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol.
Miro1-dependent mitochondrial dynamics in parvalbumin Interneurons.
The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS.
TOMM40 RNA Transcription in Alzheimer's Disease Brain and Its Implication in Mitochondrial Dysfunction.
Protective Effect of Salidroside on Mitochondrial Disturbances via Reducing Mitophagy and Preserving Mitochondrial Morphology in OGD-induced Neuronal Injury.
Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis.
Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR.
STING1 Promotes Ferroptosis Through MFN1/2-Dependent Mitochondrial Fusion.
NADH Fluorescence Lifetime Imaging Microscopy Reveals Selective Mitochondrial Dysfunction in Neurons Overexpressing Alzheimer's Disease-Related Proteins.
Exploring the Role of Autophagy Dysfunction in Neurodegenerative Disorders.
Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders.
Leber's Hereditary Optic Neuropathy: A Report on Novel mtDNA Pathogenic Variants.
AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma.
Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations.
DJ-1 in neurodegenerative diseases: pathogenesis and clinical application.
Age-dependent shift in the de novo proteome accompanies pathogenesis in an Alzheimer's disease mouse model.
Mitochondrial O-GlcNAc Transferase Interacts with and Modifies Many Proteins and Its Up-Regulation Affects Mitochondrial Function and Cellular Energy Homeostasis.
An Hsp90 co-chaperone links protein folding and degradation and is part of a conserved protein quality control.
Repeated Aconitine Treatment Induced the Remodeling of Mitochondrial Function via AMPK-OPA1-ATP5A1 Pathway.
Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function.
A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood.
Polymerase Gamma Mitochondrial DNA Depletion Syndrome Initially Presenting as Disproportionate Respiratory Distress in a Moderately Premature Neonate: A Case Report.
The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection.
Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation.

Antioxidants (Basel). 2021 Jun 10. pii: 938. [Epub ahead of print]10(6):

Effect of Chronic Stress Present in Fibroblasts Derived from Patients with a Sporadic Form of AD on Mitochondrial Function and Mitochondrial Turnover.

Karolina Drabik, Dominika Malińska, Karolina Piecyk, Grażyna Dębska-Vielhaber, Stefan Vielhaber, Jerzy Duszyński, Joanna Szczepanowska.

  Although the sporadic form of Alzheimer's disease (AD) is the prevalent form, the cellular events underlying the disease pathogenesis have not been fully characterized. Accumulating evidence points to mitochondrial dysfunction as one of the events responsible for AD progression. We investigated mitochondrial function in fibroblasts collected from patients diagnosed with the sporadic form of AD (sAD), placing a particular focus on mitochondrial turnover. We measured mitochondrial biogenesis and autophagic clearance, and evaluated the presence of bioenergetic stress in sAD cells. The mitochondrial turnover was clearly lower in the fibroblasts from sAD patients than in the fibroblasts from the control subjects, and the levels of many proteins regulating mitochondrial biogenesis, autophagy and mitophagy were decreased in patient cells. Additionally, the sAD fibroblasts had slightly higher mitochondrial superoxide levels and impaired antioxidant defense. Mitochondrial turnover undergoes feedback regulation through mitochondrial retrograde signaling, which is responsible for the maintenance of optimal mitochondrial functioning, and mitochondria-derived ROS participate as signaling molecules in this process. Our results showed that in sAD patients cells, there is a shift in the balance of mitochondrial function, possibly in response to the presence of cellular stress related to disease development.

Keywords:  Alzheimer’s disease; mitochondria; mitochondrial biogenesis; mitochondrial retrograde signaling; mitophagy; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox10060938
Redox Biol. 2021 Jun 17. pii: S2213-2317(21)00206-8. [Epub ahead of print]45 102047

Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia.

Prasad Sulkshane, Jonathan Ram, Anita Thakur, Noa Reis, Oded Kleifeld, Michael H Glickman.

  The contribution of the Ubiquitin-Proteasome System (UPS) to mitophagy has been largely attributed to the E3 ubiquitin ligase Parkin. Here we show that in response to the oxidative stress associated with hypoxia or the hypoxia mimic CoCl2, the damaged and fragmented mitochondria are removed by Parkin-independent mitophagy. Mitochondria isolated from hypoxia or CoCl2-treated cells exhibited extensive ubiquitination, predominantly Lysine 48-linked and involves the degradation of key mitochondrial proteins such as the mitofusins MFN1/2, or the import channel component TOM20. Reflecting the critical role of mitochondrial protein degradation, proteasome inhibition blocked CoCl2-induced mitophagy. The five conserved ubiquitin-binding autophagy receptors (p62, NDP52, Optineurin, NBR1, TAX1BP1) were dispensable for the ensuing mitophagy, suggesting that the mitophagy step itself was independent of ubiquitination. Instead, the expression of two ubiquitin-independent mitophagy receptor proteins BNIP3 and NIX was induced by hypoxia or CoCl2-treatment followed by their recruitment to the oxidation-damaged mitochondria. By employing BNIP3/NIX double knockout and DRP1-null cell lines, we confirmed that mitochondrial clearance relies on DRP1-dependent mitochondrial fragmentation and BNIP3/NIX-mediated mitophagy. General antioxidants such as N-Acetyl Cysteine (NAC) or the mitochondria-specific Mitoquinone prevented HIF-1α stabilization, ameliorated hypoxia-related mitochondrial oxidative stress, and suppressed mitophagy. We conclude that the UPS and receptor-mediated autophagy converge to eliminate oxidation-damaged mitochondria.

Keywords:  HIF-1α; Hypoxia; Mitochondria; Mitophagy; Oxidative stress; Proteasome; Ubiquitin

DOI:  https://doi.org/10.1016/j.redox.2021.102047
Cells. 2021 Jun 05. pii: 1395. [Epub ahead of print]10(6):

The PINK1-Mediated Crosstalk between Neural Cells and the Underlying Link to Parkinson's Disease.

Elvira Pequeno Leites, Vanessa Alexandra Morais.

  Mitochondrial dysfunction has a fundamental role in the development of idiopathic and familiar forms of Parkinson's disease (PD). The nuclear-encoded mitochondrial kinase PINK1, linked to familial PD, is responsible for diverse mechanisms of mitochondrial quality control, ATP production, mitochondrial-mediated apoptosis and neuroinflammation. The main pathological hallmark of PD is the loss of dopaminergic neurons. However, novel discoveries have brought forward the concept that a disruption in overall brain homeostasis may be the underlying cause of this neurodegeneration disease. To sustain this, astrocytes and microglia cells lacking PINK1 have revealed increased neuroinflammation and deficits in physiological roles, such as decreased wound healing capacity and ATP production, which clearly indicate involvement of these cells in the physiopathology of PD. PINK1 executes vital functions within mitochondrial regulation that have a detrimental impact on the development and progression of PD. Hence, in this review, we aim to broaden the horizon of PINK1-mediated phenotypes occurring in neurons, astrocytes and microglia and, ultimately, highlight the importance of the crosstalk between these neural cells that is crucial for brain homeostasis.

Keywords:  PINK1; Parkinson’s disease; astrocytes; microglia; mitochondrial dysfunction; neurons

DOI:  https://doi.org/10.3390/cells10061395
Sci Adv. 2021 Jul;pii: eabf8631. [Epub ahead of print]7(27):

The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication.

Min Jiang, Xie Xie, Xuefeng Zhu, Shan Jiang, Dusanka Milenkovic, Jelena Misic, Yonghong Shi, Nirwan Tandukar, Xinping Li, Ilian Atanassov, Louise Jenninger, Emily Hoberg, Sara Albarran-Gutierrez, Zsolt Szilagyi, Bertil Macao, Stefan J Siira, Valerio Carelli, Jack D Griffith, Claes M Gustafsson, Thomas J Nicholls, Aleksandra Filipovska, Nils-Göran Larsson, Maria Falkenberg.

We report a role for the mitochondrial single-stranded DNA binding protein (mtSSB) in regulating mitochondrial DNA (mtDNA) replication initiation in mammalian mitochondria. Transcription from the light-strand promoter (LSP) is required both for gene expression and for generating the RNA primers needed for initiation of mtDNA synthesis. In the absence of mtSSB, transcription from LSP is strongly up-regulated, but no replication primers are formed. Using deep sequencing in a mouse knockout model and biochemical reconstitution experiments with pure proteins, we find that mtSSB is necessary to restrict transcription initiation to optimize RNA primer formation at both origins of mtDNA replication. Last, we show that human pathological versions of mtSSB causing severe mitochondrial disease cannot efficiently support primer formation and initiation of mtDNA replication.

DOI: https://doi.org/10.1126/sciadv.abf8631
EMBO J. 2021 Jun 30. e107913

Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol.

Anna M Schlagowski, Katharina Knöringer, Sandrine Morlot, Ana Sánchez Vicente, Tamara Flohr, Lena Krämer, Felix Boos, Nabeel Khalid, Sheraz Ahmed, Jana Schramm, Lena M Murschall, Per Haberkant, Frank Stein, Jan Riemer, Benedikt Westermann, Ralf J Braun, Konstanze F Winklhofer, Gilles Charvin, Johannes M Herrmann.

  The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation-prone polyQ protein derived from human huntingtin. Expression of Q97-GFP rapidly led to insoluble cytosolic aggregates and cell death. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post-translational import of mitochondrial precursor proteins into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate-limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.

Keywords:  Mia40; huntingtin; mitochondria; protein aggregation; protein translocation

DOI:  https://doi.org/10.15252/embj.2021107913
Elife. 2021 Jun 30. pii: e65215. [Epub ahead of print]10

Miro1-dependent mitochondrial dynamics in parvalbumin Interneurons.

Georgina Kontou, Pantelis Antonoudiou, Marina Podpolny, Blanka R Szulc, I Lorena Arancibia-Carcamo, Nathalie F Higgs, Guillermo Lopez-Domenech, Patricia C Salinas, Edward Mann, Josef T Kittler.

  The spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca²⁺-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in parvalbumin interneurons and how changes in mitochondrial trafficking could alter network activity in the mouse brain. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization while PV+ interneuron mediated inhibition remained intact. These changes were accompanied by an increase in the ex vivo hippocampal γ-oscillation (30 - 80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.

Keywords:  cell biology; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.65215
Int J Mol Sci. 2021 Jun 14. pii: 6352. [Epub ahead of print]22(12):

The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS.

Elena Obrador, Rosario Salvador-Palmer, Rafael López-Blanch, Ali Jihad-Jebbar, Soraya L Vallés, José M Estrela.

  Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3-5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.

Keywords:  ALS; bioenergetics; mitochondria; oxidative stress; redox status

DOI:  https://doi.org/10.3390/ijms22126352
Genes (Basel). 2021 Jun 06. pii: 871. [Epub ahead of print]12(6):

TOMM40 RNA Transcription in Alzheimer's Disease Brain and Its Implication in Mitochondrial Dysfunction.

Eun-Gyung Lee, Sunny Chen, Lesley Leong, Jessica Tulloch, Chang-En Yu.

  Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer's disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD brains, hindering a clear interpretation of TOMM40's role in this disease. The aim of this study was to determine if TOMM40 RNA levels differ between AD and control brains. We applied RT-qPCR to study TOMM40 transcription in human postmortem brain (PMB) and assessed associations of these RNA levels with genetic variants in APOE and TOMM40. We also compared TOMM40 RNA levels with mitochondrial functions in human cell lines. Initially, we found that the human genome carries multiple TOMM40 pseudogenes capable of producing highly homologous RNAs that can obscure precise TOMM40 RNA measurements. To circumvent this obstacle, we developed a novel RNA expression assay targeting the primary transcript of TOMM40. Using this assay, we showed that TOMM40 RNA was upregulated in AD PMB. Additionally, elevated TOMM40 RNA levels were associated with decreases in mitochondrial DNA copy number and mitochondrial membrane potential in oxidative stress-challenged cells. Overall, differential transcription of TOMM40 RNA in the brain is associated with AD and could be an indicator of mitochondrial dysfunction.

Keywords:  Alzheimer’s disease; RNA transcription; TOMM40 gene; mitochondrial dysfunction; pseudogene

DOI:  https://doi.org/10.3390/genes12060871
Curr Med Sci. 2021 Jun 28.

Protective Effect of Salidroside on Mitochondrial Disturbances via Reducing Mitophagy and Preserving Mitochondrial Morphology in OGD-induced Neuronal Injury.

Cai-Ying Hu, Qian-Ying Zhang, Jie-Hui Chen, Bin Wen, Wei-Jian Hang, Kai Xu, Juan Chen, Ben-Hong He.

  Salidroside is the active ingredient extracted from Rhodiola rosea, and has been reported to show protective effects in cerebral ischemia, but the exact mechanisms of neuronal protective effects are still unrevealed. In this study, the protective effects of salidroside (1 µmol/L) in ameliorating neuronal injuries induced by oxygen-glucose deprivation (OGD), which is a classical model of cerebral ischemia, were clarified. The results showed that after 8 h of OGD, the mouse hippocampal neuronal cell line HT22 cells showed increased cell death, accompanied with mitochondrial fragmentation and augmented mitophagy. However, the cell viability of HT22 cells showed significant restoration after salidroside treatment. Mitochondrial morphology and mitochondrial function were effectively preserved by salidroside treatment. The protective effects of salidroside were further related to the prevention of mitochondrial over-fission. The results showed that mTOR could be recruited to the mitochondria after salidroside treatment, which might be responsible for inhibiting excessive mitophagy caused by OGD. Thus, salidroside was shown to play a protective role in reducing neuronal death under OGD by safeguarding mitochondrial function, which may provide evidence for further translational studies of salidroside in ischemic diseases.

Keywords:  mTOR; mitochondria quality control; oxygen-glucose deprivation; salidroside

DOI:  https://doi.org/10.1007/s11596-021-2374-6
Front Neurol. 2021 ;12 681326

Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis.

Valentina Del Dotto, Valerio Carelli.

  In the year 2000, the discovery of OPA1 mutations as causative for dominant optic atrophy (DOA) was pivotal to rapidly expand the field of mitochondrial dynamics and describe the complex machinery governing this pathway, with a multitude of other genes and encoded proteins involved in neurodegenerative disorders of the optic nerve. OPA1 turned out to be a much more complex protein than initially envisaged, connecting multiple pathways beyond its strict role in mitochondrial fusion, such as sensing of OXPHOS needs and mitochondrial DNA maintenance. As a consequence, an increasing need to investigate OPA1 functions at multiple levels has imposed the development of multiple tools and models that are here reviewed. Translational mitochondrial medicine, with the ultimate objective of translating basic science necessary to understand pathogenic mechanisms into therapeutic strategies, requires disease modeling at multiple levels: from the simplest, like in yeast, to cell models, including the increasing use of reprogrammed stem cells (iPSCs) from patients, to animal models. In the present review, we thoroughly examine and provide the state of the art of all these approaches.

Keywords:  OPA1; OPA1 mutations; cell models; dominant optic atrophy; iPSCs; mitochondria; mouse models; retinal ganglion cells

DOI:  https://doi.org/10.3389/fneur.2021.681326
PLoS Genet. 2021 Jul 02. 17(7): e1009664

Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR.

Daniel Poveda-Huertes, Asli Aras Taskin, Ines Dhaouadi, Lisa Myketin, Adinarayana Marada, Lukas Habernig, Sabrina Büttner, F-Nora Vögtle.

Mitochondrial defects can cause a variety of human diseases and protective mechanisms exist to maintain mitochondrial functionality. Imbalances in mitochondrial proteostasis trigger a transcriptional program, termed mitochondrial unfolded protein response (mtUPR). However, the temporal sequence of events in mtUPR is unclear and the consequences on mitochondrial protein import are controversial. Here, we have quantitatively analyzed all main import pathways into mitochondria after different time spans of mtUPR induction. Kinetic analyses reveal that protein import into all mitochondrial subcompartments strongly increases early upon mtUPR and that this is accompanied by rapid remodelling of the mitochondrial signature lipid cardiolipin. Genetic inactivation of cardiolipin synthesis precluded stimulation of protein import and compromised cellular fitness. At late stages of mtUPR upon sustained stress, mitochondrial protein import efficiency declined. Our work clarifies the enigma of protein import upon mtUPR and identifies sequential mtUPR stages, in which an early increase in protein biogenesis to restore mitochondrial proteostasis is followed by late stages characterized by a decrease in import capacity upon prolonged stress induction.

DOI: https://doi.org/10.1371/journal.pgen.1009664
Front Cell Dev Biol. 2021 ;9 698679

STING1 Promotes Ferroptosis Through MFN1/2-Dependent Mitochondrial Fusion.

Changfeng Li, Jiao Liu, Wen Hou, Rui Kang, Daolin Tang.

  Ferroptosis is a type of iron-dependent regulated cell death caused by the disruption that occurs when oxidative stress and antioxidant defenses interact, and then driven by lipid peroxidation and subsequent plasma membrane ruptures. The regulation of ferroptosis involves many factors, including the crosstalk between subcellular organelles, such as mitochondria, endoplasmic reticulum (ER), lysosomes, lipid droplets, and peroxisomes. Here, we show that the ER protein STING1 (also known as STING or TMEM173) promotes ferroptosis in human pancreatic cancer cell lines by increasing MFN1/2-dependent mitochondrial fusion, but not mitophagy-mediated mitochondrial removal. The classic ferroptosis inducer erastin, but not sulfasalazine, induces the accumulation of STING1 in the mitochondria, where it binds to MFN1/2 to trigger mitochondrial fusion, leading to subsequent reactive oxygen species production and lipid peroxidation. Consequently, in vitro or xenograft mouse models show that the genetic depletion of STING1 or MFN1/2 (but not the mitophagy regulator PINK1 or PRKN) reduces the sensitivity of pancreatic cancer cells to ferroptosis. These findings not only establish a new mitochondrial fusion-dependent cell death mechanism, but also indicate a potential strategy for enhancing ferroptosis-based therapy.

Keywords:  MFN1/2; STING1; dynamic; ferroptosis; mitochondria

DOI:  https://doi.org/10.3389/fcell.2021.698679
Front Mol Biosci. 2021 ;8 671274

NADH Fluorescence Lifetime Imaging Microscopy Reveals Selective Mitochondrial Dysfunction in Neurons Overexpressing Alzheimer's Disease-Related Proteins.

Moritz A Niederschweiberer, Patrick M Schaefer, Larry N Singh, Ludwig Lausser, Devyani Bhosale, Raphael Hesse, Enrico Calzia, Hans A Kestler, Angelika Rueck, Douglas C Wallace, Bjoern von Einem, Christine A F von Arnim.

  Alzheimer's disease (AD), the most prevalent form of dementia, affects globally more than 30 million people suffering from cognitive deficits and neuropsychiatric symptoms. Substantial evidence for the involvement of mitochondrial dysfunction in the development and/or progression of AD has been shown in addition to the pathological hallmarks amyloid beta (Aβ) and tau. Still, the selective vulnerability and associated selective mitochondrial dysfunction cannot even be resolved to date. We aimed at optically quantifying mitochondrial function on a single-cell level in primary hippocampal neuron models of AD, unraveling differential involvement of cell and mitochondrial populations in amyloid precursor protein (APP)-associated mitochondrial dysfunction. NADH lifetime imaging is a highly sensitive marker-free method with high spatial resolution. However, deciphering cellular bioenergetics of complex cells like primary neurons has still not succeeded yet. To achieve this, we combined highly sensitive NADH lifetime imaging with respiratory inhibitor treatment, allowing characterization of mitochondrial function down to even the subcellular level in primary neurons. Measuring NADH lifetime of the same neuron before and after respiratory treatment reveals the metabolic delta, which can be taken as a surrogate for cellular redox capacity. Correlating NADH lifetime delta with overexpression strength of Aβ-related proteins on the single-cell level, we could verify the important role of intracellular Aβ-mediated mitochondrial toxicity. Subcellularly, we could demonstrate a higher respiration in neuronal somata in general than dendrites, but a similar impairment of somatic and dendritic mitochondria in our AD models. This illustrates the power of NADH lifetime imaging in revealing mitochondrial function on a single and even subcellular level and its potential to shed light into bioenergetic alterations in neuropsychiatric diseases and beyond.

Keywords:  Alzheimer’s disease; NADH; amyloid beta; energy metabolism; mitochondria; redox imaging

DOI:  https://doi.org/10.3389/fmolb.2021.671274
Mol Neurobiol. 2021 Jul 02.

Exploring the Role of Autophagy Dysfunction in Neurodegenerative Disorders.

Tarapati Rana, Tapan Behl, Aayush Sehgal, Vineet Mehta, Sukhbir Singh, Saurabh Bhatia, Ahmed Al-Harrasi, Simona Bungau.

  Autophagy is a catabolic pathway by which misfolded proteins or damaged organelles are engulfed by autophagosomes and then transported to lysosomes for degradation. Recently, a great improvement has been done to explain the molecular mechanisms and roles of autophagy in several important cellular metabolic processes. Besides being a vital clearance pathway or a cell survival pathway in response to different stresses, autophagy dysfunction, either upregulated or down-regulated, has been suggested to be linked with numerous neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Impairment at different stages of autophagy results in the formation of large protein aggregates and damaged organelles, which leads to the onset and progression of different neurodegenerative disorders. This article elucidates the recent progress about the role of autophagy in neurodegenerative disorders and explains how autophagy dysfunction is linked with the pathogenesis of such disorders as well as the novel potential autophagy-associated therapies for treating them.

Keywords:  Autophagosome; Autophagy; Dysfunction; Neurodegenerative disorders; Pathophysiology

DOI:  https://doi.org/10.1007/s12035-021-02472-0
Int J Mol Sci. 2021 Jun 29. pii: 7030. [Epub ahead of print]22(13):

Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders.

Gonzalo E Moya, Phillip D Rivera, Kristin E Dittenhafer-Reed.

  Mitochondria are regarded as the metabolic centers of cells and are integral in many other cell processes, including the immune response. Each mitochondrion contains numerous copies of mitochondrial DNA (mtDNA), a small, circular, and bacterial-like DNA. In response to cellular damage or stress, mtDNA can be released from the mitochondrion and trigger immune and inflammatory responses. mtDNA release into the cytosol or bloodstream can occur as a response to hypoxia, sepsis, traumatic injury, excitatory cytotoxicity, or drastic mitochondrial membrane potential changes, some of which are hallmarks of neurodegenerative and mood disorders. Released mtDNA can mediate inflammatory responses observed in many neurological and mood disorders by driving the expression of inflammatory cytokines and the interferon response system. The current understanding of the role of mtDNA release in affective mood disorders and neurodegenerative diseases will be discussed.

Keywords:  inflammation; mitochondria; mitochondrial DNA (mtDNA); neurodegenerative disease; neuropsychiatric disorder; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/ijms22137030
Front Neurol. 2021 ;12 657317

Leber's Hereditary Optic Neuropathy: A Report on Novel mtDNA Pathogenic Variants.

Lorenzo Peverelli, Alessia Catania, Silvia Marchet, Paola Ciasca, Gabriella Cammarata, Lisa Melzi, Antonella Bellino, Roberto Fancellu, Eleonora Lamantea, Mariantonietta Capristo, Leonardo Caporali, Chiara La Morgia, Valerio Carelli, Daniele Ghezzi, Stefania Bianchi Marzoli, Costanza Lamperti.

  Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.

Keywords:  LHON; Leber optic atrophy; complex I; mitochondrial respiratory chain; transmitochondrial cybrids

DOI:  https://doi.org/10.3389/fneur.2021.657317
Mol Neurodegener. 2021 Jun 29. 16(1): 43

AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma.

Nicolas Belforte, Jessica Agostinone, Luis Alarcon-Martinez, Deborah Villafranca-Baughman, Florence Dotigny, Jorge L Cueva Vargas, Adriana Di Polo.

   BACKGROUND: The maintenance of complex dendritic arbors and synaptic transmission are processes that require a substantial amount of energy. Bioenergetic decline is a prominent feature of chronic neurodegenerative diseases, yet the signaling mechanisms that link energy stress with neuronal dysfunction are poorly understood. Recent work has implicated energy deficits in glaucoma, and retinal ganglion cell (RGC) dendritic pathology and synapse disassembly are key features of ocular hypertension damage.
RESULTS: We show that adenosine monophosphate-activated protein kinase (AMPK), a conserved energy biosensor, is strongly activated in RGC from mice with ocular hypertension and patients with primary open angle glaucoma. Our data demonstrate that AMPK triggers RGC dendrite retraction and synapse elimination. We show that the harmful effect of AMPK is exerted through inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Attenuation of AMPK activity restores mTORC1 function and rescues dendrites and synaptic contacts. Strikingly, AMPK depletion promotes recovery of light-evoked retinal responses, improves axonal transport, and extends RGC survival.
CONCLUSIONS: This study identifies AMPK as a critical nexus between bioenergetic decline and RGC dysfunction during pressure-induced stress, and highlights the importance of targeting energy homeostasis in glaucoma and other neurodegenerative diseases.

Keywords:  Adenosine monophosphate-activated protein kinase; Glaucoma; Mammalian target of rapamycin; Metabolic stress; Neurodegeneration

DOI:  https://doi.org/10.1186/s13024-021-00466-z
Sci Rep. 2021 Jun 30. 11(1): 13613

Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations.

Shaakir Salam, Sara Tacconelli, Bradley N Smith, Jacqueline C Mitchell, Elizabeth Glennon, Nikolas Nikolaou, Corinne Houart, Caroline Vance.

Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affecting mitochondria, synapses and the neuromuscular junction (NMJ). This indicates a crucial physiological role for FUS in regulating synaptic and mitochondrial function that is currently poorly understood. In this paper we provide evidence that mislocalised cytoplasmic FUS causes mitochondrial and synaptic changes and that FUS plays a vital role in maintaining neuronal health in vitro and in vivo. Overexpressing mutant FUS altered synaptic numbers and neuronal complexity in both primary neurons and zebrafish models. The degree to which FUS was mislocalised led to differences in the synaptic changes which was mirrored by changes in mitochondrial numbers and transport. Furthermore, we showed that FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and that mutations in FUS affect this relationship. Finally, we demonstrated mutant FUS led to changes in global protein translation. This localisation between FUS and SNPH could explain the synaptic and mitochondrial defects observed leading to global protein translation defects. Importantly, our results support the 'gain-of-function' hypothesis for disease pathogenesis in FUS-related ALS.

DOI: https://doi.org/10.1038/s41598-021-93189-6
Prog Neurobiol. 2021 Jun 23. pii: S0301-0082(21)00128-3. [Epub ahead of print] 102114

DJ-1 in neurodegenerative diseases: pathogenesis and clinical application.

Maoxin Huang, Shengdi Chen.

  Neurodegenerative diseases (NDs) are one of the major health threats to human characterized by selective and progressive neuronal loss. The mechanisms of NDs are still not fully understood. The study of genetic defects and disease-related proteins offers us a window into the mystery of it, and the extension of knowledge indicates that different NDs share similar features, mechanisms, and even genetic or protein abnormalities. Among these findings, PARK7 and its production DJ-1 protein, which was initially found implicated in PD, have also been found altered in other NDs. PARK7 mutations, altered expression and posttranslational modification (PTM) causes DJ-1 abnormalities, which in turn leads to downstream mechanisms shared by most NDs, such as mitochondrial dysfunction, oxidative stress, protein aggregation, autophagy defects, and so on. The knowledge of DJ-1 derived from PD researches might apply to other NDs in both basic research and clinical application, and might yield novel insights into and alternative approaches for dealing with NDs.

Keywords:  DJ-1; PARK7; biomarker; neurodegenerative diseases; pathogenesis; therapeutic strategy

DOI:  https://doi.org/10.1016/j.pneurobio.2021.102114
Commun Biol. 2021 Jun 30. 4(1): 823

Age-dependent shift in the de novo proteome accompanies pathogenesis in an Alzheimer's disease mouse model.

Megan K Elder, Hediye Erdjument-Bromage, Mauricio M Oliveira, Maggie Mamcarz, Thomas A Neubert, Eric Klann.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic alterations in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label and enrich newly synthesized proteins, we found that the de novo proteome is disturbed in young APP/PS1 mice prior to symptom onset, affecting the synthesis of multiple components of the synaptic, lysosomal, and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout development. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.

DOI: https://doi.org/10.1038/s42003-021-02324-6
Cancers (Basel). 2021 Jun 12. pii: 2956. [Epub ahead of print]13(12):

Mitochondrial O-GlcNAc Transferase Interacts with and Modifies Many Proteins and Its Up-Regulation Affects Mitochondrial Function and Cellular Energy Homeostasis.

Paweł Jóźwiak, Piotr Ciesielski, Piotr K Zakrzewski, Karolina Kozal, Joanna Oracz, Grażyna Budryn, Dorota Żyżelewicz, Stéphanie Flament, Anne-Sophie Vercoutter-Edouart, Fabrice Bray, Tony Lefebvre, Anna Krześlak.

  O-GlcNAcylation is a cell glucose sensor. The addition of O-GlcNAc moieties to target protein is catalyzed by the O-Linked N-acetylglucosamine transferase (OGT). OGT is encoded by a single gene that yields differentially spliced OGT isoforms. One of them is targeted to mitochondria (mOGT). Although the impact of O-GlcNAcylation on cancer cells biology is well documented, mOGT's role remains poorly investigated. We performed studies using breast cancer cells with up-regulated mOGT or its catalytic inactive mutant to identify proteins specifically modified by mOGT. Proteomic approaches included isolation of mOGT protein partners and O-GlcNAcylated proteins from mitochondria-enriched fraction followed by their analysis by mass spectrometry. Moreover, we analyzed the impact of mOGT dysregulation on mitochondrial activity and cellular metabolism using a variety of biochemical assays. We found that mitochondrial OGT expression is glucose-dependent. Elevated mOGT expression affected the mitochondrial transmembrane potential and increased intramitochondrial ROS generation. Moreover, mOGT up-regulation caused a decrease in cellular ATP level. We identified many mitochondrial proteins as mOGT substrates. Most of these proteins are localized in the mitochondrial matrix and the inner mitochondrial membrane and participate in mitochondrial respiration, fatty acid metabolism, transport, translation, apoptosis, and mtDNA processes. Our findings suggest that mOGT interacts with and modifies many mitochondrial proteins, and its dysregulation affects cellular bioenergetics and mitochondria function.

Keywords:  O-GlcNAc; breast cancer; energy metabolism; glucose; mOGT; mitochondria

DOI:  https://doi.org/10.3390/cancers13122956
Cell Rep. 2021 Jun 29. pii: S2211-1247(21)00704-X. [Epub ahead of print]35(13): 109328

An Hsp90 co-chaperone links protein folding and degradation and is part of a conserved protein quality control.

Frederik Eisele, Anna Maria Eisele-Bürger, Xinxin Hao, Lisa Larsson Berglund, Johanna L Höög, Beidong Liu, Thomas Nyström.

  In this paper, we show that the essential Hsp90 co-chaperone Sgt1 is a member of a general protein quality control network that links folding and degradation through its participation in the degradation of misfolded proteins both in the cytosol and the endoplasmic reticulum (ER). Sgt1-dependent protein degradation acts in a parallel pathway to the ubiquitin ligase (E3) and ubiquitin chain elongase (E4), Hul5, and overproduction of Hul5 partly suppresses defects in cells with reduced Sgt1 activity. Upon proteostatic stress, Sgt1 accumulates transiently, in an Hsp90- and proteasome-dependent manner, with quality control sites (Q-bodies) of both yeast and human cells that co-localize with Vps13, a protein that creates organelle contact sites. Misfolding disease proteins, such as synphilin-1 involved in Parkinson's disease, are also sequestered to these compartments and require Sgt1 for their clearance.

Keywords:  26S proteasome; Hsp90; Hul5; Sgt1; aging; chaperone; protein quality control; proteostasis

DOI:  https://doi.org/10.1016/j.celrep.2021.109328
Front Pharmacol. 2021 ;12 646121

Repeated Aconitine Treatment Induced the Remodeling of Mitochondrial Function via AMPK-OPA1-ATP5A1 Pathway.

Li-Zhen Qiu, Wei Zhou, Lan-Xin Yue, Yi-Hao Wang, Fei-Ran Hao, Peng-Yan Li, Yue Gao.

  Aconitine is attracting increasing attention for its unique positive inotropic effect on the cardiovascular system, but underlying molecular mechanisms are still not fully understood. The cardiotonic effect always requires abundant energy supplement, which is mainly related to mitochondrial function. And OPA1 has been documented to play a critical role in mitochondrial morphology and energy metabolism in cardiomyocytes. Hence, this study was designed to investigate the potential role of OPA1-mediated regulation of energy metabolism in the positive inotropic effect caused by repeated aconitine treatment and the possible mechanism involved. Our results showed that repeated treatment with low-doses (0-10 μM) of aconitine for 7 days did not induce detectable cytotoxicity and enhanced myocardial contraction in Neonatal Rat Ventricular Myocytes (NRVMs). Also, we first identified that no more than 5 μM of aconitine triggered an obvious perturbation of mitochondrial homeostasis in cardiomyocytes by accelerating mitochondrial fusion, biogenesis, and Parkin-mediated mitophagy, followed by the increase in mitochondrial function and the cellular ATP content, both of which were identified to be related to the upregulation of ATP synthase α-subunit (ATP5A1). Besides, with compound C (CC), an inhibitor of AMPK, could reverse aconitine-increased the content of phosphor-AMPK, OPA1, and ATP5A1, and the following mitochondrial function. In conclusion, this study first demonstrated that repeated aconitine treatment could cause the remodeling of mitochondrial function via the AMPK-OPA1-ATP5A1 pathway and provide a possible explanation for the energy metabolism associated with cardiotonic effect induced by medicinal plants containing aconitine.

Keywords:  ATP5A1; OPA1; aconitine; mitochondrial fusion; mitochondrial homeostasis

DOI:  https://doi.org/10.3389/fphar.2021.646121
Cells. 2021 Jun 19. pii: 1552. [Epub ahead of print]10(6):

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function.

Mariona Guitart-Mampel, Pedro Urquiza, Jordana I Borges, Anastasios Lymperopoulos, Maria E Solesio.

  The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)-particularly βARs-play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

Keywords:  G protein-coupled receptor (GPCR); adverse remodeling; aldosterone; heart failure; mineralocorticoid receptor; mitochondria; mitochondrial bioenergetics; mitochondrial dynamics; mitochondrial dysfunction; signaling crosstalk

DOI:  https://doi.org/10.3390/cells10061552
Front Neurol. 2021 ;12 675616

A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood.

Hongyan Bi, Hui Guo, Qianfei Wang, Xiao Zhang, Yaming Zhao, Jimei Li, Weiqin Zhao, Houzhen Tuo, Yongbo Zhang.

  Background: Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN results in high morbidity and mortality among infants and children, and its diagnosis is clinically challenging due to several overlapping disease phenotypes. Therefore, a precise genetic diagnosis is urgently needed for accurate genetic counseling and improved prognostic outcomes as well. Objective: To identify novel missense mutations in the NDUFAF5 gene as a cause of childhood BSN in members of a Chinese family and summarize the clinical characteristics of patients with the NDUFAF5 gene mutations. Methods: This study included a large family living in a remote northwestern area of China. Three siblings developed a neurological disorder characterized by generalized dystonia within the first decade of their lives. Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral lesions of the putamen. Biochemical and genetic approaches were used to identify the cause of BSN. Results: Sequence analysis showed no pathogenic variation in PANK2, SLC25A19, SLC19A3, and NUP62 genes and in the entire mitochondrial genome as well. Whole-exome sequencing revealed compound heterozygous mutations consisting of NDUFAF5:c.425A > C(p.E142A) and c.836T > G (p.M279R). The father, a healthy sister, and a healthy brother of the affected siblings carried the c.836T > G mutation, and the mother carried the c.425A > C mutation. These variants were absent in 100 ethnically matched non-BSN controls. In silico analysis demonstrated that the E142A and M279R mutations in NDUFAF5 protein significantly perturbed the normal conformation of the protein due to alterations in the hydrogen bonding patterns around the evolutionarily conserved catalytic domains, leading to its loss of function in the early stage of mitochondrial complex I assembly. Conclusions: We identified a novel compound heterozygous mutation (c.425A > C and c.836T > G) in the NDUFAF5 gene as the potential cause of autosomal recessive childhood BSN, which extended the pathogenic variation spectrum of the NDUFAF5 gene. This study provides substantial evidence for further improvement of genetic counseling and better clinical management of BSN affected individuals.

Keywords:  NDUFAF5; bilateral striatal necrosis; mitochondrial complex I deficiency; novel variation; whole-exome sequencing

DOI:  https://doi.org/10.3389/fneur.2021.675616
Front Genet. 2021 ;12 664278

Polymerase Gamma Mitochondrial DNA Depletion Syndrome Initially Presenting as Disproportionate Respiratory Distress in a Moderately Premature Neonate: A Case Report.

Andrew D Franklin, Bimal P Chaudhari, Daniel C Koboldt, Kerri Z Machut.

  A 32-week premature infant presented with respiratory failure, later progressing to pulmonary hypertension (PH), liver failure, lactic acidosis, and encephalopathy. Using exome sequencing, this patient was diagnosed with a rare Polymerase Gamma (POLG)-related mitochondrial DNA (mtDNA) depletion syndrome. This case demonstrates that expanding the differential to uncommon diagnoses is important for complex infants, even in premature neonates whose condition may be explained partially by their gestational age (GA). It also shows that patients with complex neonatal diseases with significant family history may benefit from exome sequencing for diagnosis.

Keywords:  case report; mitochondria DNA depletion; polymerase gamma; pulmonary hypertension; whole exome sequencing

DOI:  https://doi.org/10.3389/fgene.2021.664278
Int J Mol Sci. 2021 Jun 17. pii: 6479. [Epub ahead of print]22(12):

The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection.

Johannes Burtscher, Grégoire P Millet, Nicolas Place, Bengt Kayser, Nadège Zanou.

  Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer's disease, or the most common neurodegenerative motor disorder, Parkinson's disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle-brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle-brain axis in neurodegenerative diseases are outlined.

Keywords:  brain; exercise; mitochondria; muscle; myokines; neurodegeneration

DOI:  https://doi.org/10.3390/ijms22126479
Redox Biol. 2021 Jun 19. pii: S2213-2317(21)00211-1. [Epub ahead of print]45 102052

Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation.

Sandra Torres, Estel Solsona-Vilarrasa, Susana Nuñez, Nuria Matías, Naroa Insausti-Urkia, Fernanda Castro, Mireia Casasempere, Gemma Fabriás, Josefina Casas, Carlos Enrich, José C Fernández-Checa, Carmen Garcia-Ruiz.

  Niemann-Pick type C (NPC) disease, a lysosomal storage disorder caused by defective NPC1/NPC2 function, results in the accumulation of cholesterol and glycosphingolipids in lysosomes of affected organs, such as liver and brain. Moreover, increase of mitochondrial cholesterol (mchol) content and impaired mitochondrial function and GSH depletion contribute to NPC disease. However, the underlying mechanism of mchol accumulation in NPC disease remains unknown. As STARD1 is crucial in intramitochondrial cholesterol trafficking and acid ceramidase (ACDase) has been shown to regulate STARD1, we explored the functional relationship between ACDase and STARD1 in NPC disease. Liver and brain of Npc1-/- mice presented a significant increase in mchol levels and STARD1 expression. U18666A, an amphiphilic sterol that inhibits lysosomal cholesterol efflux, increased mchol levels in hepatocytes from Stard1f/f mice but not Stard1ΔHep mice. We dissociate the induction of STARD1 expression from endoplasmic reticulum stress, and establish an inverse relationship between ACDase and STARD1 expression and LRH-1 levels. Hepatocytes from Npc1+/+ mice treated with U18666A exhibited increased mchol accumulation, STARD1 upregulation and decreased ACDase expression, effects that were reversed by cholesterol extraction with 2-hydroxypropyl-β-cyclodextrin. Moreover, transfection of fibroblasts from NPC patients with ACDase, decreased STARD1 expression and mchol accumulation, resulting in increased mitochondrial GSH levels, improved mitochondrial functional performance, decreased oxidative stress and protected NPC fibroblasts against oxidative stress-mediated cell death. Our results demonstrate a cholesterol-dependent inverse relationship between ACDase and STARD1 and provide a novel approach to target the accumulation of cholesterol in mitochondria in NPC disease.

Keywords:  Acid ceramiase; Cholesterol; Mitochondrial function; NPC disease; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2021.102052