Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation

Feldkamp, Thorsten; Park, Jeong Soon; Pasupulati, Ratna; Amora, Daniela Nascimento; Roeser, Nancy F.; Venkatachalam, Manjeri A.; Weinberg, Joel M.

doi:10.1152/ajprenal.00422.2009

Cited by 31 publications

(35 citation statements)

References 82 publications

(188 reference statements)

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“…S2 illustrates use of changes of ⌬⌿ m and assessment of matrix volume by light scattering to follow induction of the MPT with Ca 2ϩ in permeabilized tubules from WT mice. Results were similar to our previous findings with rabbit tubules, which we described in more detail elsewhere (24). In our previous study (24), we also developed, for the permeabilized tubules, a method for measurement of medium Ca 2ϩ to follow Ca 2ϩ movements into and out of the mitochondria to allow for better quantitation of the effects of determinants of the MPT.…”

Section: Cypd Knockout Micesupporting

confidence: 87%

“…Results were similar to our previous findings with rabbit tubules, which we described in more detail elsewhere (24). In our previous study (24), we also developed, for the permeabilized tubules, a method for measurement of medium Ca 2ϩ to follow Ca 2ϩ movements into and out of the mitochondria to allow for better quantitation of the effects of determinants of the MPT. The latter approach was used for all subsequent studies comparing the MPT in tubules from WT and Ppif Ϫ/Ϫ mice.…”

Section: Cypd Knockout Micesupporting

confidence: 87%

“…Figure 1 shows representative experiments of this type comparing WT and knockout tubules. Initial uptake of Ca 2ϩ following its addition at 300 s is followed by spontaneous release as the PTP opens, precluding retention of the Ca 2ϩ (24). In tubules from Ppif Ϫ/Ϫ mice, Ca 2ϩ uptake before release is substantially greater, consistent with resistance to development of the MPT.…”

Section: Cypd Knockout Micementioning

confidence: 95%

“…Fluorescence was followed at 520-nm excitation and 520-nm emission (24,34) simultaneously with the safranin O uptake measurements of ⌬⌿ m or calcium green-5N measurements of medium Ca 2ϩ (24).…”

Section: Assessment Of Changes Of Matrix Volume By Light Scatteringmentioning

confidence: 99%

“…To better define its behavior in proximal tubule cells during acute kidney injury, we previously characterized the MPT and the effect of hypoxia-reoxygenation (H/R) on it in freshly isolated rabbit proximal tubules, which are especially sensitive to mitochondrial damage and dysfunction because of their low capacity for glycolysis (24). We found that NEFA that are endogenously generated by hypoxia prior to the MPT and produced during the MPT and dependence on complex I-requiring substrates would increase the likelihood of development of the MPT prelethally, despite ample levels of the pore antagonists ADP and Mg 2ϩ in intact cells.…”

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confidence: 99%

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Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury

Park

Pasupulati

Feldkamp

et al. 2011

American Journal of Physiology-Renal Physiology

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(MPT). Kidney proximal tubule cells are especially prone to deleterious effects of mitochondrial damage because of their dependence on oxidative mitochondrial metabolism for ATP production. To clarify the role of CyPD and the MPT in proximal tubule injury during ischemia-reperfusion (I/R) and hypoxia-reoxygenation (H/R), we assessed freshly isolated tubules and in vivo injury in wild-type (WT) and Ppif Ϫ/Ϫ CyPD-null mice. Isolated mouse tubules developed a sustained, nonesterified fatty acid-mediated energetic deficit after H/R in vitro that could be substantially reversed by delipidated albumin and supplemental citric acid cycle substrates but was not modified by the absence of CyPD. Susceptibility of WT and Ppif Ϫ/Ϫ tubules to the MPT was increased by H/R but was less in normoxic and H/R Ppif Ϫ/Ϫ than WT tubules. Correction of the energetic deficit that developed during H/R strongly increased resistance to the MPT. Ppif Ϫ/Ϫ mice were resistant to I/R injury in vivo spanning a wide range of severity. The data clarify involvement of the MPT in oxygen deprivation-induced tubule cell injury by showing that the MPT does not contribute to the initial bioenergetic deficit produced by H/R but the deficit predisposes to subsequent development of the MPT, which contributes pathogenically to kidney I/R injury in vivo.acute kidney injury; membrane potential; mitochondria THE MITOCHONDRIAL PERMEABILITY transition (MPT) results from the regulated and reversible opening of an ϳ3-nm-diameter pore in the inner mitochondrial membrane with a size exclusion limit of ϳ1.5 kDa that is frequently termed the permeability transition pore (PTP) (33,35,42,56). Sustained opening of the PTP dissipates the transmembrane ion gradients necessary for energy conservation and leads to loss of inorganic and small organic matrix solutes and matrix swelling. Pore opening can be prevented and reversed by cyclosporin A (CsA) (7, 13) via binding by CsA of a mitochondrial matrix cyclophilin D (CyPD) (2,3,36,48,57,69). Although the specific proteins forming the PTP channel have not been conclusively identified (5,35,37), multiple inducers and antagonists are known (33,35,56,72). The endogenous metabolites ADP and Mg 2ϩ and matrix acidification potently antagonize pore opening. Inducers include multiple conditions commonly present during injury states, i.e., decrease of membrane potential (⌬⌿ m ) and increase of Ca 2ϩ , phosphate, reactive oxygen species (ROS), and a number of lipid metabolites, including nonesterified fatty acids (NEFA) and their CoA and carnitine esters and ceramides (33,56,72). Recent studies have shown that phosphate, in addition to promoting the effect of Ca 2ϩ to induce the MPT, is required for MPT inhibition by CyPD (4) and have implicated the phosphate carrier as a PTP component (43).Once the glycine-sensitive plasma membrane pores that mediate necrotic cell death (16, 50) form, the MPT is promoted by influx of extracellular Ca 2ϩ and loss of cytosolic metabolites such as ADP and Mg 2ϩ , so the process predictably occurs after ...

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Section: Cypd Knockout Micesupporting

confidence: 87%

Section: Cypd Knockout Micesupporting

confidence: 87%

Section: Cypd Knockout Micementioning

confidence: 95%

Section: Assessment Of Changes Of Matrix Volume By Light Scatteringmentioning

confidence: 99%

mentioning

confidence: 99%

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Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury

Park

Pasupulati

Feldkamp

et al. 2011

American Journal of Physiology-Renal Physiology

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Pathophysiology of Acute Kidney Injury

Basile

Anderson

Sutton

2012

Comprehensive Physiology

972

906

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Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or CKD patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future.

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The role of glycine in regulated cell death

Weinberg

Bienholz

Venkatachalam

2016

Cell. Mol. Life Sci.

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The cytoprotective effects of glycine against cell death have been recognized for over 28 years. They are expressed in multiple cell types and injury settings that lead to necrosis, but are still not widely appreciated or considered in the conceptualization of cell death pathways. In this paper we review the available data on the expression of this phenomenon, its relationship to major pathophysiologic pathways that lead to cell death and immunomodulatory effects, the hypothesis that it involves suppression by glycine of the development of a hydrophilic death channel of molecular dimensions in the plasma membrane, and evidence for its impact on disease processes in vivo.

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Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation

Cited by 31 publications

References 82 publications

Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury

Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury

Pathophysiology of Acute Kidney Injury

The role of glycine in regulated cell death

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