Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney.

Hou Y, Tan E, Shi H, Ren X, Wan X, Wu W, Chen Y, Niu H, Zhu G, Li J, Li Y, Wang L

Cellular and molecular life sciences : CMLS11 Jan 2024Cited by 96 (Europe PMC)

PMID38200266PMCIDPMC10781825DOI10.1007/s00018-023-05078-yPepBankPUB-38200266

Summary

The functional and structural changes in the proximal tubule play an important role in the occurrence and development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead to changes in the state of tubular epithelial cells (TECs), and among all the disturbances in metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production of mitochondrial reactive oxygen species (mtROS), is considered one of the primary factors causing diabetic tubular injury. Most studies have discussed how altered metabolic flux drives mitochondrial oxidative stress during DKD. In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs. Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation. Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO), but had no obvious effect on major glucose metabolic rate-limiting enzymes. Mitochondrial oxidative stress facilitated renal Sphingosine-1-phosphate (S1P) deposition and SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity, and the decreased Spns2 expression. These data suggest a role of mitochondrial oxidative damage in unbalanced lipid metabolism, including lipid droplet (LD) formulation, lipid peroxidation, and impaired FAO and sphingolipid homeostasis in DKD. An in vitro study demonstrated that high glucose drove elevated expression of cytosolic phospholipase A2 (cPLA2), which, in turn, was responsible for the altered lipid metabolism, including LD generation and S1P accumulation, in HK-2 cells. A mitochondria-targeted antioxidant inhibited the activation of cPLA2f isoforms. Taken together, these findings identify mechanistic links between mitochondrial oxidative metabolism and reprogrammed lipid metabolism in diabetic TECs, and provide further evidence for the nephroprotective effects of SS31 via influencing metabolic pathways.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

5 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In the diabetic kidney, SS31 reversed the decreased expression of key enzymes and regulators of fatty acid oxidation.
In plain wordsIn diabetic kidney tissue, SS31 restored lower levels of proteins that burn fat.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseFatty acid oxidation enzymes and regulators
Study
n: not reported in source
Diabetic kidney (model not stated)
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated
Source sentences
Summary
Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO)
1 context sentence(design, population, supporting numbers)
Summary · context
In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs.
Show in the study text Report a problemFND-3820026601
02AnimalAnimal study (in vivo)Efficacy outcome
In the diabetic kidney, SS31 had no obvious effect on major glucose metabolic rate-limiting enzymes.
In plain wordsIn diabetic kidney tissue, SS31 had no clear effect on key sugar-processing enzymes.
Peptide
Elamipretide (SS-31)
Outcome
No significant changeGlucose metabolic rate-limiting enzymes
Study
n: not reported in source
Diabetic kidney (model not stated)
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated
Source sentences
Summary
but had no obvious effect on major glucose metabolic rate-limiting enzymes.
1 context sentence(design, population, supporting numbers)
Summary · context
In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs.
Show in the study text Report a problemFND-3820026602
03AnimalAnimal study (in vivo)Mechanism
In the diabetic kidney, SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity.
In plain wordsIn diabetic kidney tissue, SS31 lowered raised activity of three fat-signaling proteins.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseAcer1, S1pr1 and SPHK1 activity
Study
n: not reported in source
Diabetic kidney (model not stated)
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated
Source sentences
Summary
SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity
1 context sentence(design, population, supporting numbers)
Summary · context
In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs.
Show in the study text Report a problemFND-3820026603
04AnimalAnimal study (in vivo)Mechanism
In the diabetic kidney, SS31 limited the decrease in Spns2 expression.
In plain wordsIn diabetic kidney tissue, SS31 kept a fat-transport protein from falling as much.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseSpns2 expression
Study
n: not reported in source
Diabetic kidney (model not stated)
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated
Source sentences
Summary
and the decreased Spns2 expression.
1 context sentence(design, population, supporting numbers)
Summary · context
In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs.
Show in the study text Report a problemFND-3820026604
05AnimalAnimal study (in vivo)Mechanism
Using SS31 to protect mitochondria, the study showed that mitochondrial oxidative damage contributes to tubular epithelial cell injury and lipid peroxidation.
In plain wordsProtecting mitochondria with SS31 showed that mitochondrial damage adds to kidney cell injury in diabetes.
Peptide
Elamipretide (SS-31)
Outcome
Not applicableTubular epithelial cell injury and lipid peroxidation
Study
n: not reported in source
Diabetic kidney (model not stated)
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated
Source sentences
Summary
Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation.
1 context sentence(design, population, supporting numbers)
Summary · context
In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs.
Show in the study text Report a problemFND-3820026605

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 08:19 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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