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Succinylation of Park7 activates a protective metabolic response to acute kidney injury
Katherine Pfister1, Victoria Young1, Brendon Frankel1
1Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Abstract:
Acute kidney injury (AKI) is extremely prevalent among hospitalizations and presents a significant risk for the development of chronic kidney disease and increased mortality. Ischemia caused by shock, trauma, and transplant are common causes of AKI. To attenuate ischemic AKI therapeutically, we need a better understanding of the physiological and cellular mechanisms underlying damage. Instances of ischemia are most damaging in proximal tubule epithelial cells (PTECs) where hypoxic signaling cascades, and perhaps more rapidly, posttranslational modifications (PTMs), act in concert to change cellular metabolism. Here, we focus on the effects of the understudied PTM, lysine succinylation. We have previously shown a protective effect of protein hypersuccinylation on PTECs after depletion of the desuccinylase sirtuin5. General trends in the results suggested that hypersuccinylation led to upregulation of peroxisomal activity and was protective against kidney injury. Included in the list of changes was the Parkinson's-related deglycase Park7. There is little known about any links between peroxisome activity and Park7. In this study, we show in vitro and in vivo that Park7 has a crucial role in protection from AKI and upregulated peroxisome activity. These data in combination with published results of Park7's protective role in cardiovascular damage and chronic kidney disease lead us to hypothesize that succinylation of Park7 may ameliorate oxidative damage resulting from AKI and prevent disease progression. This novel mechanism provides a potential therapeutic mechanism that can be targeted.NEW & NOTEWORTHY Succinylation is an understudied posttranslational modification that has been shown to increase peroxisomal activity. Furthermore, increased peroxisomal activity has been shown to reduce oxidative stress and protect proximal tubules after acute kidney injury. Analysis of mass spectrometry succinylomic and proteomic data reveals a novel role for Parkinson's related Park7 in mediating Nrf2 antioxidant response after kidney injury. This novel protection pathway provides new insights for kidney injury prevention and development of novel therapeutics.
Insights
Lysine succinylation, a posttranslational modification, enhances peroxisomal activity and protects against acute kidney injury (AKI). The Parkinson's-related protein Park7 plays a key role in this protective mechanism, offering new therapeutic targets for kidney disease.
Area of Science:
- Biochemistry
- Cell Biology
- Nephrology
Background:
- Acute kidney injury (AKI) is a prevalent condition associated with high mortality and progression to chronic kidney disease.
- Ischemic AKI, often caused by shock or trauma, primarily damages kidney proximal tubule epithelial cells (PTECs).
- Posttranslational modifications (PTMs), such as lysine succinylation, are increasingly recognized for their role in cellular metabolism and response to injury.
Purpose of the Study:
- To investigate the role of lysine succinylation in PTEC protection during AKI.
- To elucidate the function of the Parkinson's-related protein Park7 in AKI pathogenesis and peroxisomal activity.
- To explore the potential of succinylation as a therapeutic strategy for preventing AKI and its progression.
Main Methods:
- In vitro and in vivo studies were conducted to assess the effects of lysine succinylation on PTECs.
- Mass spectrometry-based succinylomic and proteomic analyses were employed to identify changes in protein succinylation and expression.
- Park7's role in AKI and peroxisome activity was evaluated using cellular and animal models.
Main Results:
- Lysine hypersuccinylation was found to upregulate peroxisomal activity in PTECs.
- Park7 was identified as a crucial mediator of protection against AKI and was linked to upregulated peroxisome activity.
- Data suggest Park7's involvement in the Nrf2 antioxidant response pathway following kidney injury.
Conclusions:
- Lysine succinylation, particularly involving Park7, represents a novel protective mechanism against ischemic AKI.
- Targeting Park7 succinylation may offer a therapeutic avenue to ameliorate oxidative damage and prevent kidney disease progression.
- This study highlights an underappreciated PTM and protein in kidney injury, opening new possibilities for therapeutic development.
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