Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

Hernando‐Rodríguez, Blanca; Artal‐Sanz, Marta

doi:10.3390/cells7120238

Cited by 66 publications

(40 citation statements)

References 130 publications

(214 reference statements)

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“…PHB is a mitochondrial protein which has emerged as an important modulator of neuronal survival in different injury models (Zhou et al, 2012; Hernando-Rodríguez and Artal-Sanz, 2018). PHB localizes to the inner membrane of mitochondria acting as a chaperone protein, but is also found in the nucleus, where it negatively regulates transcription.…”

Section: Discussionmentioning

confidence: 99%

“…PHB is a pleiotropic multifaceted protein and an essential factor in mitochondrial homeostasis, biogenesis, degradation, and response to stress (Peng et al, 2015; Ande et al, 2017; Hernando-Rodríguez and Artal-Sanz, 2018). In mitochondria, PHB acts as a scaffold protein and is thus crucial for regulation of mitochondrial architecture, mitochondrial dynamics, morphology, and biogenesis, and furthermore stabilizes the mitochondrial genome (Merkwirth et al, 2012; Peng et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Curcumin: Novel Treatment in Neonatal Hypoxic-Ischemic Brain Injury

Rocha‐Ferreira

Sisa²,

Bright³

et al. 2019

Front. Physiol.

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Hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and morbidity in neonates, with an estimated global incidence of 3/1,000 live births. HIE brain damage is associated with an inflammatory response and oxidative stress, resulting in the activation of cell death pathways. At present, therapeutic hypothermia is the only clinically approved treatment available for HIE. This approach, however, is only partially effective. Therefore, there is an unmet clinical need for the development of novel therapeutic interventions for the treatment of HIE. Curcumin is an antioxidant reactive oxygen species scavenger, with reported anti-tumor and anti-inflammatory activity. Curcumin has been shown to attenuate mitochondrial dysfunction, stabilize the cell membrane, stimulate proliferation, and reduce injury severity in adult models of spinal cord injury, cancer, and cardiovascular disease. The role of curcumin in neonatal HIE has not been widely studied due to its low bioavailability and limited aqueous solubility. The aim of this study was to investigate the effect of curcumin treatment in neonatal HIE, including time of administration and dose-dependent effects. Our results indicate that curcumin administration prior to HIE in neonatal mice elevated cell and tissue loss, as well as glial activation compared to HI alone. However, immediate post-treatment with curcumin was significantly neuroprotective, reducing grey and white matter tissue loss, TUNEL+ cell death, microglia activation, reactive astrogliosis, and iNOS oxidative stress when compared to vehicle-treated littermates. This effect was dose-dependent, with 200 μg/g body weight as the optimal dose-regimen, and was maintained when curcumin treatment was delayed by 60 or 120 min post-HI. Cell proliferation measurements showed no changes between curcumin and HI alone, suggesting that the protective effects of curcumin on the neonatal brain following HI are most likely due to curcumin’s anti-inflammatory and antioxidant properties, as seen in the reduced glial and iNOS activity. In conclusion, this study suggests curcumin as a potent neuroprotective agent with potential for the treatment of HIE. The delayed application of curcumin further increases its clinical relevance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Curcumin: Novel Treatment in Neonatal Hypoxic-Ischemic Brain Injury

Rocha‐Ferreira

Sisa²,

Bright³

et al. 2019

Front. Physiol.

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“…Interestingly, an increased level of the PHB complex has been reported under UPR mt activation as depending on imbalance in the synthesis of mitochondrial- and nuclear-encoded mitochondrial proteins, in mammals [60] and C. elegans [13], or on accumulation of unassembled subunits of respiratory chain, in yeast [61]. In C. elegans , it is also reported that the lack of PHB induces a strong UPR mt activation (reviewed in [62]). This enforces the role of PHBs in the mitochondrial protein quality control.…”

Section: Role Of Prohibitins In Unfolded Protein Response (Uprmt)mentioning

confidence: 99%

Prohibitins: A Critical Role in Mitochondrial Functions and Implication in Diseases

Signorile

Sgaramella

Bellomo

et al. 2019

Cells

160

159

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Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are proteins that are ubiquitously expressed, and are present in the nucleus, cytosol, and mitochondria. Depending on the cellular localization, PHB1 and PHB2 have distinctive functions, but more evidence suggests a critical role within mitochondria. In fact, PHB proteins are highly expressed in cells that heavily depend on mitochondrial function. In mitochondria, these two proteins assemble at the inner membrane to form a supra-macromolecular structure, which works as a scaffold for proteins and lipids regulating mitochondrial metabolism, including bioenergetics, biogenesis, and dynamics in order to determine the cell fate, death, or life. PHB alterations have been found in aging and cancer, as well as neurodegenerative, cardiac, and kidney diseases, in which significant mitochondrial impairments have been observed. The molecular mechanisms by which prohibitins regulate mitochondrial function and their role in pathology are reviewed and discussed herein.

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“…Kathiria et al [62] show that PHB1 knockdown generates reactive oxygen species, mitochondrial depolarization, and induced autophagy. In Hernando-Rodríguez and Artal-Sanz [63], several phenotypes of PHB are reviewed, including the role of PHB in mitochondrial stability. PHB has also been implicated in the inflammatory response in both the lung and gut [63,64].…”

Section: Nonstructural Protein 2 (Nsp2)mentioning

confidence: 99%

Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models

et al. 2020

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Background A mechanistic understanding of the spread of SARS-CoV-2 and diligent tracking of ongoing mutagenesis are of key importance to plan robust strategies for confining its transmission. Large numbers of available sequences and their dates of transmission provide an unprecedented opportunity to analyze evolutionary adaptation in novel ways. Addition of high-resolution structural information can reveal the functional basis of these processes at the molecular level. Integrated systems biology-directed analyses of these data layers afford valuable insights to build a global understanding of the COVID-19 pandemic. Results Here we identify globally distributed haplotypes from 15,789 SARS-CoV-2 genomes and model their success based on their duration, dispersal, and frequency in the host population. Our models identify mutations that are likely compensatory adaptive changes that allowed for rapid expansion of the virus. Functional predictions from structural analyses indicate that, contrary to previous reports, the Asp614Gly mutation in the spike glycoprotein (S) likely reduced transmission and the subsequent Pro323Leu mutation in the RNA-dependent RNA polymerase led to the precipitous spread of the virus. Our model also suggests that two mutations in the nsp13 helicase allowed for the adaptation of the virus to the Pacific Northwest of the USA. Finally, our explainable artificial intelligence algorithm identified a mutational hotspot in the sequence of S that also displays a signature of positive selection and may have implications for tissue or cell-specific expression of the virus. Conclusions These results provide valuable insights for the development of drugs and surveillance strategies to combat the current and future pandemics.

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Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

Cited by 66 publications

References 130 publications

Curcumin: Novel Treatment in Neonatal Hypoxic-Ischemic Brain Injury

Curcumin: Novel Treatment in Neonatal Hypoxic-Ischemic Brain Injury

Prohibitins: A Critical Role in Mitochondrial Functions and Implication in Diseases

Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models

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