Knockout of cyclophilin D in Ppif−/− mice increases stability of brain mitochondria against Ca2+ stress

Gainutdinov, T. M.; Molkentin, Jeffery D.; Siemen, Detlef; Ziemer, Mirjam; Dębska–Vielhaber, Grażyna; Vielhaber, Stefan; Gizatullina, Zemfira; Orynbayeva, Zulfiya; Gellerich, Frank N.

doi:10.1016/j.abb.2015.05.009

Cited by 21 publications

(22 citation statements)

References 49 publications

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“…We did not observe any change in mitochondrial calcium under these conditions ( Figure 2K), suggesting that mPTP formation is required for the mitochondrial calcium release after nerve injury. To go further and confirm the role of mPTP, we also used a cyclophilin D knockout mouse model (referred to herein as CypD -/mice) (31,32). Cyclophilin D is a protein required for mPTP formation (31,32).…”

Section: Characterization Of Mitochondrial Physiology During Demyelinmentioning

confidence: 99%

“…To go further and confirm the role of mPTP, we also used a cyclophilin D knockout mouse model (referred to herein as CypD -/mice) (31,32). Cyclophilin D is a protein required for mPTP formation (31,32). We injected viruses expressing mito-GCaMP2, cyto-GCaMP2, or mito-SypHer into the sciatic nerves of these mice, and then we crushed the nerves in order to follow mitochondrial physiology during demyelination.…”

Section: Characterization Of Mitochondrial Physiology During Demyelinmentioning

confidence: 99%

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Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

González¹,

Berthelot²,

Jiner³

et al. 2016

Journal of Clinical Investigation

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Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondrial calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondrial calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies.

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Section: Characterization Of Mitochondrial Physiology During Demyelinmentioning

confidence: 99%

Section: Characterization Of Mitochondrial Physiology During Demyelinmentioning

confidence: 99%

Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

González¹,

Berthelot²,

Jiner³

et al. 2016

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…The efflux of Ca 2+ occurs through a transient or low conductance opening of mPTP, most likely by lower oligomeric states of mPTP [ 13 , 131 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ]. The evidence for transient opening of mPTP for Ca 2+ was demonstrated by the early studies on the inhibition of Ca 2+ release by Cyclosporin A in isolated adult rat ventricular cardiomyocytes [ 133 ].…”

Section: Calcium Transport Systems In Mitochondriamentioning

confidence: 99%

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

Naumova

Šachl

2020

Membranes

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Mitochondria represent the fundamental system for cellular energy metabolism, by not only supplying energy in the form of ATP, but also by affecting physiology and cell death via the regulation of calcium homeostasis and the activity of Bcl-2 proteins. A lot of research has recently been devoted to understanding the interplay between Bcl-2 proteins, the regulation of these interactions within the cell, and how these interactions lead to the changes in calcium homeostasis. However, the role of Bcl-2 proteins in the mediation of mitochondrial calcium homeostasis, and therefore the induction of cell death pathways, remain underestimated and are still not well understood. In this review, we first summarize our knowledge about calcium transport systems in mitochondria, which, when miss-regulated, can induce necrosis. We continue by reviewing and analyzing the functions of Bcl-2 proteins in apoptosis. Finally, we link these two regulatory mechanisms together, exploring the interactions between the mitochondrial Ca2+ transport systems and Bcl-2 proteins, both capable of inducing cell death, with the potential to determine the cell death pathway—either the apoptotic or the necrotic one.

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“…Another orphan putatively involved in calcium signalling is hPPIF, the human homolog of yCpr1. In a study using mice as a model system, the importance of this protein and its involvement in the permeability transition pore, thereby regulating calcium levels, are investigated [98]. Regulation of Ca 2 + levels in mitochondria is a critically important task.…”

Section: Ims Candidates For Calcium Homeostasis Alzheimer's Disease mentioning

confidence: 99%

Orphan proteins of unknown function in the mitochondrial intermembrane space proteome: New pathways and metabolic cross-talk

Nuebel

Manganas

Tokatlidis

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The mitochondrial intermembrane space (IMS) is involved in protein transport, lipid homeostasis and metal ion exchange, while further acting in signalling pathways such as apoptosis. Regulation of these processes involves protein modifications, as well as stress-induced import or release of proteins and other signalling molecules. Even though the IMS is the smallest sub-compartment of mitochondria, its redox state seems to be tightly regulated. However, the way in which this compartment participates in the cross-talk between the multiple organelles and the cytosol is far from understood. Here we focus on newly identified IMS proteins that may represent future challenges in mitochondrial research. We present an overview of the import pathways, the recently discovered new components of the IMS proteome and how these relate to key aspects of cell signalling and progress made in stem cell and cancer research.

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Knockout of cyclophilin D in Ppif−/− mice increases stability of brain mitochondria against Ca2+ stress

Cited by 21 publications

References 49 publications

Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

Orphan proteins of unknown function in the mitochondrial intermembrane space proteome: New pathways and metabolic cross-talk

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