Morphological principles of neuronal mitochondria

Mendelsohn, Rachel; García, Guadalupe C.; Bartol, Thomas M.; Lee, Christopher T.; Khandelwal, Priya; Liu, Emily; Spencer, Donald; Husar, Adam; Bushong, Eric A.; Phan, Sébastien; Perkins, Guy; Ellisman, Mark H.; Skupin, Alexander; Sejnowski, Terrence J.; Rangamani, Padmini

doi:10.1002/cne.25254

Cited by 19 publications

(18 citation statements)

References 71 publications

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“…The pera membrane density in these sulfate-reducing bacteria ( Fig. 6E ) was 5 to 10 times lower than that typically observed for metazoan crista membrane density ( 44 – 47 ). This lower density can be attributed to the finding that either the pera did not extend far into the interior, as was typical for the T3B1 pera ( Fig.…”

Section: Discussionmentioning

confidence: 51%

A Cristae-Like Microcompartment in Desulfobacterota

McGlynn

Perkins

Sim

et al. 2022

mBio

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Working with anaerobic consortia of methane oxidizing ANME archaea and their sulfate-reducing bacterial partners recovered from deep sea sediments and with the related sulfate-reducing bacterial isolate D. carbinolicus , we discovered that their intracytoplasmic membranes (ICMs) appear remarkably similar to lamellar cristae. Three-dimensional electron microscopy allowed for the novel analysis of the nanoscale attachment of ICMs to the cytoplasmic membrane, and these ICMs are structurally nearly identical to the crista junction architecture seen in metazoan mitochondria.

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Section: Discussionmentioning

confidence: 51%

A Cristae-Like Microcompartment in Desulfobacterota

McGlynn

Perkins

Sim

et al. 2022

mBio

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“…The IMM is just one example of a highly curved membrane in cells; others include narrow tubules in the peripheral ER 126 and rims of Golgi cisternae 127 . A common feature across these organelles is that regions of very high curvature are present alongside those with low curvatures 7,128,129 . While relevant curvature-inducing proteins have been identified in these structures, how bimodal distributions of curvature are stabilized within the same continuous lipid membrane is less clear.…”

Section: Discussionmentioning

confidence: 99%

Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome

Venkatraman

Lee

García

et al. 2023

Preprint

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The inner mitochondrial membrane (IMM) is the site of bulk ATP generation in cells and has a broadly conserved lipid composition enriched in unsaturated phospholipids and cardiolipin (CL). While proteins that shape the IMM and its characteristic cristae membranes (CM) have been defined, specific mechanisms by which mitochondrial lipids dictate its structure and function have yet to be elucidated. Here we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions shape CM morphology and ATP generation. When modulating fatty acid unsaturation in engineered yeast strains, we observed that loss of di-unsaturated phospholipids (PLs) led to a breakpoint in IMM topology and respiratory capacity. We found that PL unsaturation modulates the organization of ATP synthases that shape cristae ridges. Based on molecular modeling of mitochondrial-specific membrane adaptations, we hypothesized that conical lipids like CL buffer against the effects of saturation on the IMM. In cells, we discovered that loss of CL collapses the IMM at intermediate levels of PL saturation, an effect that is independent of ATP synthase oligomerization. To explain this interaction, we employed a continuum modeling approach, finding that lipid and protein-mediated curvatures are predicted to act in concert to form curved membranes in the IMM. The model highlighted a snapthrough instability in cristae tubule formation, which could drive IMM collapse upon small changes in composition. The interaction between CL and di-unsaturated PLs suggests that growth conditions that alter the fatty acid pool, such as oxygen availability, could define CL function. While loss of CL only has a minimal phenotype under standard laboratory conditions, we show that its synthesis is essential under microaerobic conditions that better mimic natural yeast fermentation. Lipid and protein-mediated mechanisms of curvature generation can thus act together to support mitochondrial architecture under changing environments.

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“…Further, globular shaped mitochondria could also be a favorable adaptation as it is recently shown that, in comparison to elongated mitochondria, globular mitochondria contain densely packed cristae membranes with high curvature. As ATP synthase is known to localize at intense curvature in cristae, globular mitochondria might possess better energetic capabilities [83,84]. Further ultrastructural analysis along with mitochondrial activity assays may shed light on this possibility.…”

Section: Plos Geneticsmentioning

confidence: 99%

Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC

et al. 2023

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Cells under mitochondrial stress often co-opt mechanisms to maintain energy homeostasis, mitochondrial quality control and cell survival. A mechanistic understanding of such responses is crucial for further insight into mitochondrial biology and diseases. Through an unbiased genetic screen in Drosophila, we identify that mutations in lrpprc2, a homolog of the human LRPPRC gene that is linked to the French-Canadian Leigh syndrome, result in PINK1-Park activation. While the PINK1-Park pathway is well known to induce mitophagy, we show that PINK1-Park regulates mitochondrial dynamics by inducing the degradation of the mitochondrial fusion protein Mitofusin/Marf in lrpprc2 mutants. In our genetic screen, we also discover that Bendless, a K63-linked E2 conjugase, is a regulator of Marf, as loss of bendless results in increased Marf levels. We show that Bendless is required for PINK1 stability, and subsequently for PINK1-Park mediated Marf degradation under physiological conditions, and in response to mitochondrial stress as seen in lrpprc2. Additionally, we show that loss of bendless in lrpprc2 mutant eyes results in photoreceptor degeneration, indicating a neuroprotective role for Bendless-PINK1-Park mediated Marf degradation. Based on our observations, we propose that certain forms of mitochondrial stress activate Bendless-PINK1-Park to limit mitochondrial fusion, which is a cell-protective response.

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Morphological principles of neuronal mitochondria

Cited by 19 publications

References 71 publications

A Cristae-Like Microcompartment in Desulfobacterota

A Cristae-Like Microcompartment in Desulfobacterota

Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome

Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC

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