GAK and PRKCD kinases regulate basal mitophagy

Munson, Michael J.; Mathai, Benan John; Ng, Matthew Yoke Wui; Trachsel-Moncho, Laura; Ballina, Laura Rodríguez de la; Simonsen, Anne

doi:10.1080/15548627.2021.2015154

Cited by 13 publications

(11 citation statements)

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“…Mitophagy was assessed using the pH‐dependent mito‐Keima (mt‐Keima) reporter and confocal microscopy to detect mito‐lysosomes (Sun et al , 2017 ). To ensure that the contribution of Parkin‐dependent mitophagy was excluded, mitophagy assays were conducted using U2OS or HeLa cells, with low or no Parkin expression respectively (Tang et al , 2017 ; Munson et al , 2022 ).…”

Section: Resultsmentioning

confidence: 99%

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

et al. 2023

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To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady‐state conditions to fine‐tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F‐box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4‐associated mtDNA depletion syndrome.

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Section: Resultsmentioning

confidence: 99%

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

et al. 2023

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“…Recently, the confirmation of Prkcd localization in mitochondria and its involvement in Prkn -independent mitophagy [ 23 , 24 ] unveiled its possible role in a depressive disorder [ 25 , 26 ]. While Prkcd exemplifies a mitophagy performed by microglia/immune-competent cells (Munson et al, 2021, 2022) [ 23 , 24 ], it confirms playing a distinct role in the brain, being a striatum/amygdale-specific marker in a range of previous studies on MDD [ 19 , 20 ]. It is characteristic of multiple psychiatric statuses, including Early-Life Anxious Temperament [ 21 , 22 ] and depression/suicide behavior [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

“…Figure 7 a features two samples (aggressive, n23, depressive, n26) with distinct elevated mitophagy cycles. The aggressive one (n23) features a canonical mitophagy cycle based on Pink1-Parkn ( Park2 ) tandem, while the loser species (n26) features a Prkn -independent mitophagy cycle based on the Gak-Prkcd interaction reported quite recently [ 23 , 24 ].…”

Section: Resultsmentioning

confidence: 99%

Brain-Region-Specific Genes Form the Major Pathways Featuring Their Basic Functional Role: Their Implication in Animal Chronic Stress Model

Babenko,

Redina,

Smagin

et al. 2024

IJMS

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The analysis of RNA-Sec data from murine bulk tissue samples taken from five brain regions associated with behavior and stress response was conducted. The focus was on the most contrasting brain region-specific genes (BRSG) sets in terms of their expression rates. These BRSGs are identified as genes with a distinct outlying (high) expression rate in a specific region compared to others used in the study. The analysis suggested that BRSG sets form non-randomly connected compact gene networks, which correspond to the major neuron-mediated functional processes or pathways in each brain region. The number of BRSGs and the connection rate were found to depend on the heterogeneity and coordinated firing rate of neuron types in each brain region. The most connected pathways, along with the highest BRSG number, were observed in the Striatum, referred to as Medium Spiny Neurons (MSNs), which make up 95% of neurons and exhibit synchronous firing upon dopamine influx. However, the Ventral Tegmental Area/Medial Raphe Nucleus (VTA/MRN) regions, although primarily composed of monoaminergic neurons, do not fire synchronously, leading to a smaller BRSG number. The Hippocampus (HPC) region, on the other hand, displays significant neuronal heterogeneity, with glutamatergic neurons being the most numerous and synchronized. Interestingly, the two monoaminergic regions involved in the study displayed a common BRSG subnetwork architecture, emphasizing their proximity in terms of axonal throughput specifics and high-energy metabolism rates. This finding suggests the concerted evolution of monoaminergic neurons, leading to unique adaptations at the genic repertoire scale. With BRSG sets, we were able to highlight the contrasting features of the three groups: control, depressive, and aggressive mice in the animal chronic stress model. Specifically, we observed a decrease in serotonergic turnover in both the depressed and aggressive groups, while dopaminergic emission was high in both groups. There was also a notable absence of dopaminoceptive receptors on the postsynaptic membranes in the striatum in the depressed group. Additionally, we confirmed that neurogenesis BRSGs are specific to HPC, with the aggressive group showing attenuated neurogenesis rates compared to the control/depressive groups. We also confirmed that immune-competent cells like microglia and astrocytes play a crucial role in depressed phenotypes, including mitophagy-related gene Prkcd. Based on this analysis, we propose the use of BRSG sets as a suitable framework for evaluating case–control group-wise assessments of specific brain region gene pathway responses.

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“…Mitophagy was assessed using the pH-sensitive mito-Keima (mt-Keima) reporter and confocal microscopy to detect mito-lysosomes (Sun et al , 2017). To avoid contributions from Parkin-mitophagy, U2OS or HeLa cells were used for mitophagy assays, with low or no Parkin expression, respectively (Munson et al , 2022; Tang et al , 2017).…”

Section: Resultsmentioning

confidence: 99%

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Pagan

Nguyen‐Dien

Kozul

et al. 2022

Preprint

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Cells selectively remove damaged or excessive mitochondria through mitophagy, a specialized form of autophagy, to maintain mitochondrial quality and quantity. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation, and mitochondrial damage. However, the mechanisms by which cells remove specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box protein ubiquitin ligase complex, localizes to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that, unlike wild-type FBXL4, pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13), do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism that actively suppresses mitophagy via preventing NIX and BNIP3 accumulation and propose that excessive basal mitophagy in the FBXL4-associated mtDNA depletion syndrome is caused by dysregulation of NIX and BNIP3 turnover.

show abstract

GAK and PRKCD kinases regulate basal mitophagy

Cited by 13 publications

References 1 publication

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Brain-Region-Specific Genes Form the Major Pathways Featuring Their Basic Functional Role: Their Implication in Animal Chronic Stress Model

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

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