bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022–01–16
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
  2. Mitochondria shed their outer membrane in response to infection-induced stress.
  3. Mitochondrial Retinopathies.
  4. Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease.
  5. Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.
  6. Therapeutic applications of mitochondrial transplantation.
  7. Mitochondrial RNA processing defect caused by a SUPV3L1 mutation in two siblings with a novel neurodegenerative syndrome.
  8. Targeting and Insertion of Membrane Proteins in Mitochondria.
  9. Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.
  10. Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)/PEO-Plus Due to TWNK Mutations.
  11. Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
  12. Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors.
  13. Rapidly Progressive Spastic Paraplegia Due to Hyperhomocysteinemia in Child with MTHFR Gene Mutation and Mitochondrial Complex I Deficiency: A Rare Association.
  14. Molecular Mechanisms and Regulation of Mammalian Mitophagy.
  15. Kearns-Sayre syndrome: expanding spectrum of a "novel" mitochondrial leukomyeloencephalopathy.
  16. Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis.
  17. Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.
  18. Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
  19. Biochemical and biophysical features of disease-associated tau mutants V363A and V363I.
  20. The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions.
  21. Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation.
  22. Recent advances in, and challenges of, designing OMA1 drug screens.
  23. DRP1 interacts directly with BAX to induce its activation and apoptosis.
  24. Oocytes from Stem Cells.
  25. Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics.
  1. Cell Metab. 2022 Jan 07. pii: S1550-4131(21)00636-7. [Epub ahead of print]
    Mosaic dysfunction of mitophagy in mitochondrial muscle disease.
    Takayuki Mito, Amy E Vincent, Julie Faitg, Robert W Taylor, Nahid A Khan, Thomas G McWilliams, Anu Suomalainen.
      Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.
    Keywords:  SBFSEM; centrally nucleated fibers; lysosome; mito-QC; mitochondrial disease; mitochondrial myopathy; mitophagy; patient; ragged-red fibers
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.017
  2. Science. 2022 Jan 14. 375(6577): eabi4343
    Mitochondria shed their outer membrane in response to infection-induced stress.
    Xianhe Li, Julian Straub, Tânia Catarina Medeiros, Chahat Mehra, Fabian den Brave, Esra Peker, Ilian Atanassov, Katharina Stillger, Jonas Benjamin Michaelis, Emma Burbridge, Colin Adrain, Christian Münch, Jan Riemer, Thomas Becker, Lena F Pernas.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abi4343
  3. Int J Mol Sci. 2021 Dec 25. pii: 210. [Epub ahead of print]23(1):
    Mitochondrial Retinopathies.
    Massimo Zeviani, Valerio Carelli.
      The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns-Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.
    Keywords:  Kearns-Sayre syndrome; Leber’s hereditary optic neuropathy (LHON); ataxia and retinitis pigmentosa (NARP); autosomal dominant optic atrophy (ADOA); mitochondrial DNA; mitochondrial disorders; mtDNA heteroplasmic deletions; neurogenic muscle weakness; optic atrophy; retina; retinitis pigmentosa
    DOI:  https://doi.org/10.3390/ijms23010210
  4. Hum Mol Genet. 2022 Jan 13. pii: ddac002. [Epub ahead of print]
    Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease.
    Florian A Schober, Jia Xin Tang, Kate Sergeant, Marco F Moedas, Charlotte M Zierz, David Moore, Conrad Smith, David Lewis, Nishan Guha, Sila Hopton, Gavin Falkous, Amanda Lam, Angela Pyle, Joanna Poulton, Gráinne S Gorman, Robert W Taylor, Christoph Freyer, Anna Wredenberg.
      The SLC25A26 gene encodes a mitochondrial inner membrane carrier that transports S-adenosylmethionine (SAM) into the mitochondrial matrix in exchange for S-adenosylhomocysteine (SAH). SAM is the predominant methyl-group donor for most cellular methylation processes, of which SAH is produced as a by-product. Pathogenic, bi-allelic SLC25A26 variants are a recognised cause of mitochondrial disease in children, with a severe neonatal-onset caused by decreased SAM transport activity. Here, we describe two, unrelated adult cases, one of whom presented with recurrent episodes of severe abdominal pain and metabolic decompensation with lactic acidosis. Both patients had exercise intolerance and mitochondrial myopathy associated with bi-allelic variants in SLC25A26 which led to marked respiratory chain deficiencies and mitochondrial histopathological abnormalities in skeletal muscle that are comparable to those previously described in early-onset cases. We demonstrate using both mouse and fruit fly models that impairment of SAH, rather than SAM, transport across the mitochondrial membrane is likely the cause of this milder, late-onset phenotype. Our findings associate a novel pathomechanism with a known disease-causing protein and highlight the quests of precision medicine in optimising diagnosis, therapeutic intervention, and prognosis.
    DOI:  https://doi.org/10.1093/hmg/ddac002
  5. Front Cell Dev Biol. 2021 ;9 767407
    Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.
    Martine Uittenbogaard, Kuntal Sen, Matthew Whitehead, Christine A Brantner, Yue Wang, Lee-Jun Wong, Andrea Gropman, Anne Chiaramello.
      In this study, we aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband's pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel 1H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology. Whole exome sequencing revealed three heterozygous nuclear variants mapping in three distinct genes known to cause Leigh syndrome. Our mitochondrial bioenergetic investigations revealed an impaired mitochondrial energy metabolism. The proband's overall ATP deficit is further intensified by an ineffective metabolic reprogramming between oxidative phosphorylation and glycolysis. The deficient metabolic adaptability and global energy deficit correlate with the proband's neurological symptoms congruent with an atypical Leigh syndrome. In conclusion, our study provides much needed insights to support the development of molecular diagnostic and therapeutic strategies for atypical Leigh syndrome.
    Keywords:  combined oxidative phosphorylation deficiency; leigh syndrome; metabolic adaptability; mitochondrial energy metabolism; nuclear variants; whole exome sequencing
    DOI:  https://doi.org/10.3389/fcell.2021.767407
  6. Biochimie. 2022 Jan 10. pii: S0300-9084(22)00002-5. [Epub ahead of print]
    Therapeutic applications of mitochondrial transplantation.
    Oner Ulger, Gokhan Burcin Kubat.
      This review aims to make a framework of exogenous healthy mitochondrial transplantation and to assemble present information for improving new therapeutic applications in a variety of diseases. Recently, the significance of mitochondrial transplantation has been emphasized in a variety of mitochondrial dysfunction-related diseases such as neurodegenerative diseases, toxic injury, ischemia, cardiovascular diseases. We describe the natural mitochondrial transfer mechanisms (ie. TNT, EVs, mitochondrial dynamics), mitochondrial isolation process for transplantation (ie. source of mitochondria, requirements for successful isolation), mitochondrial transplantation methods (in vivo, in vitro), the effects and limitations of mitochondrial transplantation. Since mitochondrial transplantation is seen as an innovative potential treatment for diseases that can not be treated at the desired level, we expect to represent how the mitochondrial transplantation methods can be used in different diseases.
    Keywords:  Mitochondria dysfunction; Mitochondrial dynamics; Mitochondrial isolation; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.biochi.2022.01.002
  7. J Inherit Metab Dis. 2022 Jan 13.
    Mitochondrial RNA processing defect caused by a SUPV3L1 mutation in two siblings with a novel neurodegenerative syndrome.
    S L van Esveld, R J Rodenburg, F Al-Murshedi, E Al-Ajmi, S Al-Zuhaibi, M A Huynen, J N Spelbrink.
      SUPV3L1 encodes a helicase that is mainly localised in the mitochondria. It has been shown in vitro to possess both double-stranded RNA and DNA unwinding activity that is ATP-dependent. Here we report the first two patients for this gene who presented with a homozygous preliminary stop codon in the C-terminus of SUPV3L1. They presented with a characteristic phenotype of neurodegenerative nature with progressive spastic paraparesis, growth restriction, hypopigmentation, and predisposition to autoimmune disease. Ophthalmological examination showed severe photophobia with corneal erosions, optic atrophy, and pigmentary retinopathy, while neuroimaging showed atrophy of the optic chiasm and the pons with calcification of putamina, with intermittent and mild elevation of lactate. We show that the amino acids that are eliminated by the preliminary stop codon are highly conserved and are predicted to form an amphipathic helix. To investigate if the mutation causes mitochondrial dysfunction, we examined fibroblasts of the proband. We observed very low expression of the truncated protein, a reduction in the mature ND6 mRNA species as well as the accumulation of double stranded RNA. Lentiviral complementation with the full-length SUPV3L1 cDNA partly restored the observed RNA phenotypes, supporting that the SUPV3L1 mutation in these patients is pathogenic and the cause of the disease. This article is protected by copyright. All rights reserved.
    Keywords:  SUPV3L1; degradosome; mitochondrial RNA processing; mitochondrial disease; mtDNA; neurodegenerative syndrome
    DOI:  https://doi.org/10.1002/jimd.12476
  8. Front Cell Dev Biol. 2021 ;9 803205
    Targeting and Insertion of Membrane Proteins in Mitochondria.
    Ross Eaglesfield, Kostas Tokatlidis.
      Mitochondrial membrane proteins play an essential role in all major mitochondrial functions. The respiratory complexes of the inner membrane are key for the generation of energy. The carrier proteins for the influx/efflux of essential metabolites to/from the matrix. Many other inner membrane proteins play critical roles in the import and processing of nuclear encoded proteins (∼99% of all mitochondrial proteins). The outer membrane provides another lipidic barrier to nuclear-encoded protein translocation and is home to many proteins involved in the import process, maintenance of ionic balance, as well as the assembly of outer membrane components. While many aspects of the import and assembly pathways of mitochondrial membrane proteins have been elucidated, many open questions remain, especially surrounding the assembly of the respiratory complexes where certain highly hydrophobic subunits are encoded by the mitochondrial DNA and synthesised and inserted into the membrane from the matrix side. This review will examine the various assembly pathways for inner and outer mitochondrial membrane proteins while discussing the most recent structural and biochemical data examining the biogenesis process.
    Keywords:  assembly; membrane proteins; mitochondria; mitochondrial chaperones; translocons
    DOI:  https://doi.org/10.3389/fcell.2021.803205
  9. Int J Mol Sci. 2021 Dec 21. pii: 7. [Epub ahead of print]23(1):
    Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.
    Anna M Lenkiewicz, Magda Krakowczyk, Piotr Bragoszewski.
      With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.
    Keywords:  mitochondrial biogenesis; molecular chaperone; proteasome; protein degradation; protein precursor; protein transport; proteostasis; quality control; ubiquitin
    DOI:  https://doi.org/10.3390/ijms23010007
  10. J Clin Med. 2021 Dec 22. pii: 22. [Epub ahead of print]11(1):
    Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)/PEO-Plus Due to TWNK Mutations.
    Laura Bermejo-Guerrero, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Pablo Serrano-Lorenzo, Alberto Blázquez-Encinar, Gerardo Gutiérrez-Gutiérrez, Laura Martínez-Vicente, Lucía Galán-Dávila, Jorge García-García, Joaquín Arenas, Nuria Muelas, Aurelio Hernández-Laín, Cristina Domínguez-González, Miguel A Martín.
      Autosomal dominant mutations in the TWNK gene, which encodes a mitochondrial DNA helicase, cause adult-onset progressive external ophthalmoplegia (PEO) and PEO-plus presentations. In this retrospective observational study, we describe clinical and complementary data from 25 PEO patients with mutations in TWNK recruited from the Hospital 12 de Octubre Mitochondrial Disorders Laboratory Database. The mean ages of onset and diagnosis were 43 and 63 years, respectively. Family history was positive in 22 patients. Ptosis and PEO (92% and 80%) were the most common findings. Weakness was present in 48%, affecting proximal limbs, neck, and bulbar muscles. Exercise intolerance was present in 28%. Less frequent manifestations were cardiac (24%) and respiratory (4%) involvement, neuropathy (8%), ataxia (4%), and parkinsonism (4%). Only 28% had mild hyperCKemia. All 19 available muscle biopsies showed signs of mitochondrial dysfunction. Ten different TWNK mutations were identified, with c.1361T>G (p.Val454Gly) and c.1070G>C (p.Arg357Pro) being the most common. Before definitive genetic confirmation, 56% of patients were misdiagnosed (36% with myasthenia, 20% with oculopharyngeal muscle dystrophy). Accurate differential diagnosis and early confirmation with appropriately chosen complementary studies allow genetic counseling and the avoidance of unnecessary treatments. Thus, mitochondrial myopathies must be considered in PEO/PEO-plus presentations, and particularly, TWNK is an important cause when positive family history is present.
    Keywords:  TWNK gene; mitochondrial dysfunction; mtDNA maintenance defects; progressive external ophthalmoplegia
    DOI:  https://doi.org/10.3390/jcm11010022
  11. Brain. 2022 Jan 13. pii: awab488. [Epub ahead of print]
    Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
    Zhenyu Chen, Eric Chai, Yongchao Mou, Ricardo H Roda, Craig Blackstone, Xue-Jun Li.
      Hereditary spastic paraplegias (HSPs) are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive HSPs, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons (PNs) and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament (NF) aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates NF disruption in both SPG11 and SPG48 knockdown cortical PNs, confirming the contribution of HSP gene deficiency to subsequent NF and mitochondrial defects. Strikingly, NF aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical PNs. Reduced ATP levels and accumulated NF aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wildtype SPG11 in cortical PNs derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and NF aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.
    Keywords:  axonal degeneration; cortical projection neuron; cytoskeletal organization; hereditary spastic paraplegias; mitochondrial dynamics
    DOI:  https://doi.org/10.1093/brain/awab488
  12. Free Radic Biol Med. 2022 Jan 06. pii: S0891-5849(22)00001-6. [Epub ahead of print]180 33-51
    Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors.
    Zhibin Liang, David Soriano-Castell, Devin Kepchia, Brendan M Duggan, Antonio Currais, David Schubert, Pamela Maher.
      The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway can be used to identify novel drug candidates for the treatment of age-associated neurodegenerative diseases that act by preserving mitochondrial function. Previously, we identified cannabinol (CBN) as a potent neuroprotector. Here, we demonstrate that not only does CBN protect nerve cells from oxytosis/ferroptosis in a manner that is dependent on mitochondria and it does so independently of cannabinoid receptors. Specifically, CBN directly targets mitochondria and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis. These protective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP-activated protein kinase (AMPK) signaling. Together, our data highlight the potential of mitochondrially-targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction as well as opportunities for the discovery and development of future neurotherapeutics.
    Keywords:  AMPK; Aging; Antioxidant defense; Cannabinoid; Mitochondrial dysfunction; Neurodegenerative disease; Neurotherapeutics; Oxytosis/ferroptosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.001
  13. J Pediatr Neurosci. 2021 Apr-Jun;16(2):16(2): 153-155
    Rapidly Progressive Spastic Paraplegia Due to Hyperhomocysteinemia in Child with MTHFR Gene Mutation and Mitochondrial Complex I Deficiency: A Rare Association.
    Rohan R Mahale, Jyothi Gautam, Gautam Arunachal, Sandhya Alappati, Nibu Varghese, Jennifer Kovoor, Pooja Mailankody, Hansashree Padmanabha, Mathuranath Pavagada.
      MTHFR enzyme deficiency is an autosomal-recessive inborn error of folate metabolism. The deficiency cause defect in the remethylation of homocysteine to methionine leading to increased blood levels of homocysteine. Hyperhomocysteinemia in infants cause seizures, hypotonia, apnoea, microcephaly, progressing to coma and death if untreated whereas in childhood onset it causes developmental delay, seizures, psychiatric disturbances, spastic gait, and ataxia. We report a 10-year-old girl with rapidly progressive spastic paraplegia requiring wheelchair ambulation within 3 months of symptom onset with behavioral disturbances. Plasma homocysteine and plasma lactate were high with normal vitamin B12 levels. Clinical exome sequencing showed homozygous missense mutation in MTHFR gene which was likely pathogenic variant. Respiratory chain complex assay from muscle sample showed reduced complex 1 deficiency (<20%).
    Keywords:  Complex 1; MTHFR gene; mitochondria; spastic paraplegia
    DOI:  https://doi.org/10.4103/jpn.JPN_96_20
  14. Cells. 2021 Dec 23. pii: 38. [Epub ahead of print]11(1):
    Molecular Mechanisms and Regulation of Mammalian Mitophagy.
    Vinay Choubey, Akbar Zeb, Allen Kaasik.
      Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.
    Keywords:  BNIP3; FUNDC1; PARKIN; PINK1; Parkinson’s disease; autophagy; cardiolipin; mitophagy; quality control
    DOI:  https://doi.org/10.3390/cells11010038
  15. Neurol Sci. 2022 Jan 14.
    Kearns-Sayre syndrome: expanding spectrum of a "novel" mitochondrial leukomyeloencephalopathy.
    Moscatelli Marco, Ardissone Anna, Lamantea Eleonora, Zorzi Giovanna, Bruno Claudio, Moroni Isabella, Erbetta Alessandra, Chiapparini Luisa.
      Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease associated to a widespread cerebral leukodystrophy. MRI shows a typical centripetal pattern where U-fibers are mainly affected with a relative spare of periventricular white matter. Recently, different patterns of spinal cord involvement have been described in KSS. Here we report 4 new cases with typical cerebral leukodystrophy associated with spinal cord lesions. A pattern characterized by abnormal signal intensity in the H gray matter and posterior columns was found in 2 patients, while the remaining 2 presented a peculiar involvement of the spinal trigeminal nuclei at the junction of low medulla and cervical cord. MRI spinal cord involvement in KSS is probably an underestimated finding and should be evaluated in the diagnostic work up of these patients.
    Keywords:  Kearns-Sayre syndrome; Leukodystrophy; MRI; Mitochondrial disease; Spinal cord
    DOI:  https://doi.org/10.1007/s10072-022-05881-8
  16. Cells. 2021 Dec 23. pii: 30. [Epub ahead of print]11(1):
    Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis.
    Roberto Iorio, Giuseppe Celenza, Sabrina Petricca.
      Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5'-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1-Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.
    Keywords:  AMPK; E3 ligases; PINK1–Parkin pathway; Parkin activation; ULK1; mitochondria; mitophagy; mitophagy receptors; ubiquitin
    DOI:  https://doi.org/10.3390/cells11010030
  17. JCI Insight. 2022 Jan 11. pii: e150041. [Epub ahead of print]
    Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.
    Yae-Huei Liou, Jean Personnaz, David Jacobi, Nelson H Knudsen, Mayer M Chalom, Kyle A Starost, Israel C Nnah, Chih-Hao Lee.
      Mitophagy and mitochondrial integrated stress response (ISR) are two primary protective mechanisms to maintain functional mitochondria. Whether these two processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 over-expression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD fed mice. RNA-seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I stimulated genes through Atf5, which inhibits the transactivation activity of Irf3 known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 over-expression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.
    Keywords:  Glucose metabolism; Metabolism; Mitochondria; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.150041
  18. Autophagy. 2022 Jan 14. 1-2
    Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
    Melissa Vos, Christine Klein.
      Mitophagy and energy production are two functionalities in which PINK1 plays a key role. Loss of PINK1 is one of the genetic causes of Parkinson disease (PD), suggesting both processes are important in PD pathogenesis. Nonetheless, it remains unclear whether these processes are connected or independent of one another. Sphingolipids, including ceramide, have recently emerged as an important new player in the development of PD, however, how alterations in ceramide levels are mechanistically linked to PD remained elusive. In a recently published study, we demonstrated that ceramide accumulates in mitochondria and initiates ceramide-induced mitophagy, thereby compensating for the lack of PINK1-dependent mitophagy upon PINK1 deficiency. However, ceramide accumulation negatively affects ß-oxidation, further aggravating the electron transport chain (ETC) defect caused by PINK1 deficiency and resulting in an additional requirement for mitophagy. Thus, we showed that ceramide serves as a link between the ETC and mitophagy upon PINK1 deficiency. Interruption of this vicious cycle via stimulation of ß-oxidation or reduction of ceramide levels can provide a novel therapeutic target in the treatment of PINK1-related PD.
    Keywords:  PINK1; Parkinson’s disease; ceramide; mitophagy; ß-oxidation
    DOI:  https://doi.org/10.1080/15548627.2022.2027193
  19. Biochim Biophys Acta Proteins Proteom. 2022 Jan 05. pii: S1570-9639(22)00002-4. [Epub ahead of print]1870(3): 140755
    Biochemical and biophysical features of disease-associated tau mutants V363A and V363I.
    Ada De Luigi, Laura Colombo, Luca Russo, Caterina Ricci, Antonio Bastone, Sara Cimini, Fabrizio Tagliavini, Giacomina Rossi, Laura Cantù, Elena Del Favero, Mario Salmona.
      The comprehension of pathogenetic mechanisms in tauopathy-associated neurodegenerative diseases can be improved by the knowledge of the biochemical and biophysical features of mutated tau proteins. Here, we used the full-length, wild-type tau, the V363A and V363I mutated species, associated with pathology, and the P301L mutated tau as a benchmark. Using several techniques, including small-angle X-ray scattering, atomic force microscopy, thioflavin T binding, and electrophoretic separation, we compared their course from intrinsically disordered monomers in solution to early-stage recruitment in complexes and then aggregates of increasing size over long periods up to the asymptotic aggregative behavior of full-length tau proteins. We showed that diversity in the kinetics of recruitment and aggregate structure occurs from the beginning and spreads all over their pathway to very large objects. The different extents of conformational changes and types of molecular assemblies among the proteins were also reflected in their in vitro toxicity; this variation could correlate with physiopathology in humans, considering that the P301L mutation is more aggressive than V363A, especially V363I. This study identified the presence of aggregation intermediates and corroborated the oligomeric hypothesis of tauopathies.
    Keywords:  Aggregation; Fibrils; Mutation; Oligomers; Tau protein; Tauopathy
    DOI:  https://doi.org/10.1016/j.bbapap.2022.140755
  20. Int J Mol Sci. 2021 Dec 23. pii: 128. [Epub ahead of print]23(1):
    The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions.
    Francesco Pallotti, Christian Bergamini, Costanza Lamperti, Romana Fato.
      Coenzyme Q (CoQ) is a key component of the respiratory chain of all eukaryotic cells. Its function is closely related to mitochondrial respiration, where it acts as an electron transporter. However, the cellular functions of coenzyme Q are multiple: it is present in all cell membranes, limiting the toxic effect of free radicals, it is a component of LDL, it is involved in the aging process, and its deficiency is linked to several diseases. Recently, it has been proposed that coenzyme Q contributes to suppressing ferroptosis, a type of iron-dependent programmed cell death characterized by lipid peroxidation. In this review, we report the latest hypotheses and theories analyzing the multiple functions of coenzyme Q. The complete knowledge of the various cellular CoQ functions is essential to provide a rational basis for its possible therapeutic use, not only in diseases characterized by primary CoQ deficiency, but also in large number of diseases in which its secondary deficiency has been found.
    Keywords:  LDL; OxPhos; age-related diseases; coenzyme Q10; mitochondria; statins; ubiquinol-10; ubiquinone-10
    DOI:  https://doi.org/10.3390/ijms23010128
  21. Nat Commun. 2022 Jan 10. 13(1): 139
    Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation.
    Mariya Misheva, Konstantinos Kotzamanis, Luke C Davies, Victoria J Tyrrell, Patricia R S Rodrigues, Gloria A Benavides, Christine Hinz, Robert C Murphy, Paul Kennedy, Philip R Taylor, Marcela Rosas, Simon A Jones, James E McLaren, Sumukh Deshpande, Robert Andrews, Nils Helge Schebb, Magdalena A Czubala, Mark Gurney, Maceler Aldrovandi, Sven W Meckelmann, Peter Ghazal, Victor Darley-Usmar, Daniel A White, Valerie B O'Donnell.
      Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.
    DOI:  https://doi.org/10.1038/s41467-021-27766-8
  22. Pharmacol Res. 2022 Jan 06. pii: S1043-6618(22)00008-1. [Epub ahead of print] 106063
    Recent advances in, and challenges of, designing OMA1 drug screens.
    Marcel V Alavi.
      The proteases of the mitochondrial inner membrane are challenging yet highly desirable drug targets for complex, multifactorial diseases prevalent mainly in the elderly. Among them, OMA1 with its substrates OPA1 and DELE1 safeguards mitochondrial homeostasis at the intersection of energy metabolism and apoptosis, which may have relevance for neurodegeneration, malignancy and heart failure, among other diseases. Little is known about OMA1. Its structure has not been solved and we are just beginning to understand the enzyme's context-dependent regulation. OMA1 appears dormant under physiological conditions as judged by OPA1's processing pattern. The protease is rapidly activated, however, when cells experience stress or undergo apoptosis. Intriguingly, genetic OMA1 ablation can delay or even prevent apoptosis in animal models for diseases that can be broadly categorized as ischemia-reperfusion related disorders. Three groups have reported their efforts implementing OMA1 drug screens. This article reviews some of the technical challenges encountered in these assays and highlights what can be learned for future screening campaigns, and about the OMA1 protease more broadly. OMA1 does not exists in a vacuum and potent OMA1 inhibitors are needed to tease apart OMA1's intricate interactions with the other mitochondrial proteases and enzymes. Furthermore, OMA1 inhibitors hold the promise of becoming a new class of cytoprotective medicines for disorders influenced by dysfunctional mitochondria, such as heart failure or Alzheimer's Disease.
    Keywords:  AZD1080 (PubChem CID: 135564570); CCCP (PubChem CID: 2603); Ceritinib (PubChem CID: 57379345); MG132 (PubChem CID: 462382); SB216763 (PubChem CID: 176158); Sorafenib (PubChem CID: 216239); Tamoxifen (PubChem CID: 2733526); Valinomycin (PubChem CID: 3000706); cancer; drug discovery; membrane proteases; mitochondria; neurodegeneration; protease inhibitors
    DOI:  https://doi.org/10.1016/j.phrs.2022.106063
  23. EMBO J. 2022 Jan 13. e108587
    DRP1 interacts directly with BAX to induce its activation and apoptosis.
    Andreas Jenner, Aida Peña-Blanco, Raquel Salvador-Gallego, Begoña Ugarte-Uribe, Cristiana Zollo, Tariq Ganief, Jan Bierlmeier, Marcus Mund, Jason E Lee, Jonas Ries, Dirk Schwarzer, Boris Macek, Ana J Garcia-Saez.
      The apoptotic executioner protein BAX and the dynamin-like protein DRP1 co-localize at mitochondria during apoptosis to mediate mitochondrial permeabilization and fragmentation. However, the molecular basis and functional consequences of this interplay remain unknown. Here, we show that BAX and DRP1 physically interact, and that this interaction is enhanced during apoptosis. Complex formation between BAX and DRP1 occurs exclusively in the membrane environment and requires the BAX N-terminal region, but also involves several other BAX surfaces. Furthermore, the association between BAX and DRP1 enhances the membrane activity of both proteins. Forced dimerization of BAX and DRP1 triggers their activation and translocation to mitochondria, where they induce mitochondrial remodeling and permeabilization to cause apoptosis even in the absence of apoptotic triggers. Based on this, we propose that DRP1 can promote apoptosis by acting as noncanonical direct activator of BAX through physical contacts with its N-terminal region.
    Keywords:  BCL-2 proteins; fluorescence correlation spectroscopy; membrane protein complex; mitochondrial division; super-resolution microscopy
    DOI:  https://doi.org/10.15252/embj.2021108587
  24. N Engl J Med. 2022 Jan 13. 386(2): 188-190
    Oocytes from Stem Cells.
    Mary Herbert, Azim Surani.
      
    DOI:  https://doi.org/10.1056/NEJMcibr2112049
  25. J Clin Med. 2021 Dec 27. pii: 135. [Epub ahead of print]11(1):
    Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics.
    Kuan-Chou Chen, Chang-Rong Chen, Chang-Yu Chen, Chiung-Chi Peng, Robert Y Peng.
      Bicalutamide (Bic) is an androgen deprivation therapy (ADT) for treating prostate cancer, while ADT is potentially associated with acute kidney injury. Previously, we recognized Bic induced renal mitochondria dysfunction in vitro and in vivo via the ROS -HIF1α pathway. Whether OXPHOS complex, as well as mitochondrial dynamics, can be influenced by Bic via modulation of peroxisome proliferator-activated receptor coactivator 1α (PGC1α), NADPH oxidase 4 (Nox4), mitofusins 1/2 (MFN 1/2), optic atrophy 1 (OPA1), and sirtuins (SIRTs) has not been documented. Renal mesangial cell line was treated with Bic (30~60 μM) for the indicated time. SIRTs, complex I, mitochondrial dynamics- and oxidative stress-related proteins were analyzed. Bic dose-dependently reduced mitochondrial potential, but dose- and time-dependently suppressed translocase of the outer mitochondrial membrane member 20 (Tomm 20), complex I activity. Nox4 and glutathione lead to decreased NAD+/NADH ratio, with upregulated superoxide dismutase 2. SIRT1 was initially stimulated and then suppressed, while SIRT3 was time- and dose-dependently downregulated. PGC1α, MFN2, and OPA1 were all upregulated, with MFN1 and pro-fission dynamin-related protein I downregulated. Bic exhibits potential to damage mitochondria via destroying complex I, complex I activity, and mitochondrial dynamics. Long-term treatment with Bic should be carefully followed up.
    Keywords:  NADPH oxidase 4 (Nox4); PGC1α; bicalutamide; complex I NDUFB8; glutathione (GSH); mitofusins 1/2 (MFN 1/2); optic atrophy 1 (OPA1); sirtuins (SIRTs)1/3; superoxide dismutase 2 (SOD2)
    DOI:  https://doi.org/10.3390/jcm11010135
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