Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

Ilacqua, Nicolò; Anastasia, Irene; Aloshyn, Danylo; Ghandehari-Alavijeh, Rana; Peluso, Emily Ann; Brearley-Sholto, Madelaine C.; Pellegrini, Leonardo V.; Raimondi, Andrea; Vallim, Thomas Q. de Aguiar

doi:10.1186/s13062-022-00344-8

Cited by 11 publications

(6 citation statements)

References 66 publications

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“…In contrast, SYNJ2BP KO led to a reduction in the number of PLA foci per cell, indicating a decrease number of MERCs ( Fig 7I and J ). Together these results confirm that the quantity of MERCs is proportional to the level of SYNJ2BP expression ( Ilacqua et al, 2022 ; Pourshafie et al, 2022 ), which therefore strongly influences mitochondrial Ca 2+ uptake capacity.…”

Section: Resultssupporting

confidence: 73%

“…Quantitative analysis, using confocal microscopy to compare control, SYNJ2BP KO, and SYNJ2BP overexpressing fibroblasts, demonstrated that the presence of ESYT1 at mitochondria is dependent on SYNJ2BP expression ( Fig 3C ). In contrast to SYNJ2BP overexpression, loss of SYNJ2BP which decreased MERCs ( Ilacqua et al, 2022 ; Pourshafie et al, 2022 ) was associated with a decreased localization of ESYT1 at mitochondria.…”

Section: Resultsmentioning

confidence: 73%

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ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis

Janer,

Morris,

Krols

et al. 2023

Life Sci. Alliance

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Mitochondria interact with the ER at structurally and functionally specialized membrane contact sites known as mitochondria–ER contact sites (MERCs). Combining proximity labelling (BioID), co-immunoprecipitation, confocal microscopy and subcellular fractionation, we found that the ER resident SMP-domain protein ESYT1 was enriched at MERCs, where it forms a complex with the outer mitochondrial membrane protein SYNJ2BP. BioID analyses using ER-targeted, outer mitochondrial membrane-targeted, and MERC-targeted baits, confirmed the presence of this complex at MERCs and the specificity of the interaction. Deletion of ESYT1 or SYNJ2BP reduced the number and length of MERCs. Loss of the ESYT1–SYNJ2BP complex impaired ER to mitochondria calcium flux and provoked a significant alteration of the mitochondrial lipidome, most prominently a reduction of cardiolipins and phosphatidylethanolamines. Both phenotypes were rescued by reexpression of WT ESYT1 and an artificial mitochondria–ER tether. Together, these results reveal a novel function for ESYT1 in mitochondrial and cellular homeostasis through its role in the regulation of MERCs.

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Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 73%

ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis

Janer,

Morris,

Krols

et al. 2023

Life Sci. Alliance

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“…In addition, while MAM contacts ER “loosely” (gap distance of ≥10 nm), liver mitochondria are also contacted by tightly-adhering ER (“wrappER”) that is distinct from MAM [ 340 ], with essentially no gaps between the two organelles. WrappER mediates the biogenesis of lipids and lipoproteins [ 341 ] and plays an important role in cholesterol synthesis and trafficking via three-way ER-mitochondria-peroxisome contacts [ 342 ]. Taken together, these results are not only consistent with the concept that AD is indeed a lipid disorder, but also imply that in the context of AD pathology, the C99-cholesterol axis may not be confined to the brain.…”

Section: Tissue Specificitymentioning

confidence: 99%

Towards a Unitary Hypothesis of Alzheimer’s Disease Pathogenesis

Area-Gomez,

Schon

2024

JAD

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The “amyloid cascade” hypothesis of Alzheimer’s disease (AD) pathogenesis invokes the accumulation in the brain of plaques (containing the amyloid-β protein precursor [AβPP] cleavage product amyloid-β [Aβ]) and tangles (containing hyperphosphorylated tau) as drivers of pathogenesis. However, the poor track record of clinical trials based on this hypothesis suggests that the accumulation of these peptides is not the only cause of AD. Here, an alternative hypothesis is proposed in which the AβPP cleavage product C99, not Aβ, is the main culprit, via its role as a regulator of cholesterol metabolism. C99, which is a cholesterol sensor, promotes the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a cholesterol-rich lipid raft-like subdomain of the ER that communicates, both physically and biochemically, with mitochondria. We propose that in early-onset AD (EOAD), MAM-localized C99 is elevated above normal levels, resulting in increased transport of cholesterol from the plasma membrane to membranes of intracellular organelles, such as ER/endosomes, thereby upregulating MAM function and driving pathology. By the same token, late-onset AD (LOAD) is triggered by any genetic variant that increases the accumulation of intracellular cholesterol that, in turn, boosts the levels of C99 and again upregulates MAM function. Thus, the functional cause of AD is upregulated MAM function that, in turn, causes the hallmark disease phenotypes, including the plaques and tangles. Accordingly, the MAM hypothesis invokes two key interrelated elements, C99 and cholesterol, that converge at the MAM to drive AD pathogenesis. From this perspective, AD is, at bottom, a lipid disorder.

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“…Qualitatively, we found that wrappER exists in both 3-month and 2-year murine liver tissue (Figures 3G'-H'), but in 3-month tissue wrappER contact is much more extensive (Figures 3G"-H"). This suggests that liver lipid homeostasis may be negatively impacted (63)(64)(65). However, to confirm these changes and further explore the implications of these mitochondrial morphological alterations, we analyzed metabolism and performed lipidomics in mice.…”

Section: Ultrastructural Changes In Murine Liver Reveals Aging Is Ass...mentioning

confidence: 99%

MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes

Vue,

Murphy,

et al. 2024

Preprint

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The liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques.Graphical AbstractLiver aging causes metabolic, lipidomic, and mitochondrial structural alterations, reflecting age-dependent losses in the MICOS complex. Diet-dependent losses of the SAM complex underlie genetic disease associations and mitochondrial structure.

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Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

Cited by 11 publications

References 66 publications

ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis

ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis

Towards a Unitary Hypothesis of Alzheimer’s Disease Pathogenesis

MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes

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