Related Experiment Video

Updated: Aug 6, 2026

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
07:35

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess

Published on: June 1, 2022

TPI1 Loss Triggers a Metabolite-Driven Mitochondrial Redox Vulnerability via the SARM1-cADPR-Ca2+ Axis

Chunyu Liu1,2, Shun Wu1,2, Chuang Wang1,2

  • 1Senior Department of Urology, Chinese PLA General Hospital, Beijing, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 17, 2026
PubMed

Insights

Triosephosphate isomerase 1 (TPI1) depletion triggers cancer cell senescence by linking glycolytic metabolite buildup to mitochondrial redox stress. This TPI1-SARM1-cADPR-Ca2+ axis reveals a metabolic vulnerability for cancer therapy.

Area of Science:

  • Metabolic regulation of cellular processes
  • Cancer biology and redox signaling
  • Cellular senescence mechanisms

Background:

  • Cellular senescence is a key anti-cancer mechanism, but the metabolic drivers of senescence remain unclear.
  • Understanding how metabolic changes induce redox-dependent senescence is crucial for cancer therapeutics.
  • Triosephosphate isomerase 1 (TPI1) role in senescence is not well-defined.

Purpose of the Study:

  • To identify metabolic regulators of senescence in clear cell renal cell carcinoma (ccRCC).
  • To elucidate the molecular mechanisms linking metabolic perturbations to redox-dependent senescence.
  • To explore the therapeutic potential of targeting the identified metabolic-redox axis in cancer.

Main Methods:

  • CRISPR-Cas9 metabolic screening to identify senescence regulators.
  • Analysis of TPI1 depletion effects on cell cycle arrest, mitochondrial function, and DNA damage.
  • Investigation of the SARM1-cADPR-Ca2+-mtROS signaling pathway.
  • Pharmacological and genetic inhibition of calcium signaling and mitochondrial ROS.

Main Results:

  • TPI1 depletion induces senescence characterized by mitochondrial redox imbalance, DNA damage, and growth arrest.
  • Loss of TPI1 leads to dihydroxyacetone phosphate (DHAP) accumulation, activating SARM1-dependent signaling.
  • The TPI1-SARM1-cADPR-Ca2+-mtROS axis drives senescence via p53-p21 activation.
  • Inhibition of calcium signaling or mtROS partially rescues senescence phenotypes.

Conclusions:

  • A novel TPI1-SARM1-cADPR-Ca2+ axis links glycolytic metabolite accumulation to mitochondrial redox stress and senescence.
  • Metabolite-driven redox stress represents a vulnerability exploitable in cancer therapy.
  • This metabolic-redox signaling cascade is conserved across multiple cancer types.
Keywords:
TPI1cADPRcalciumcancersenescence

Related Concept Videos

Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
Mitochondrial Membranes01:45

Mitochondrial Membranes

A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...