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Published on: July 4, 2017
PNPT1 Release from Mitochondria during Apoptosis Triggers Decay of Poly(A) RNAs
Xing Liu1, Rui Fu1, Youdong Pan2
1Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Widespread mRNA decay, an unappreciated feature of apoptosis, enhances cell death and depends on mitochondrial outer membrane permeabilization (MOMP), TUTases, and DIS3L2. Which RNAs are decayed and the decay-initiating event are unknown. Here, we show extensive decay of mRNAs and poly(A) noncoding (nc)RNAs at the 3' end, triggered by the mitochondrial intermembrane space 3'-to-5' exoribonuclease PNPT1, released during MOMP. PNPT1 knockdown inhibits apoptotic RNA decay and reduces apoptosis, while ectopic expression of PNPT1, but not an RNase-deficient mutant, increases RNA decay and cell death. The 3' end of PNPT1 substrates thread through a narrow channel. Many non-poly(A) ncRNAs contain 3'-secondary structures or bind proteins that may block PNPT1 activity. Indeed, mutations that disrupt the 3'-stem-loop of a decay-resistant ncRNA render the transcript susceptible, while adding a 3'-stem-loop to an mRNA prevents its decay. Thus, PNPT1 release from mitochondria during MOMP initiates apoptotic decay of RNAs lacking 3'-structures.
Insights
Mitochondrial release of PNPT1 triggers widespread RNA decay during apoptosis, enhancing cell death. This process targets specific RNAs, revealing a new mechanism in programmed cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Widespread mRNA decay is a key, yet understudied, component of apoptosis.
- Apoptotic RNA decay relies on mitochondrial outer membrane permeabilization (MOMP), TUTases, and DIS3L2.
- The specific RNAs targeted and the initiating event of apoptotic decay remain largely unknown.
Purpose of the Study:
- To identify the RNAs undergoing decay during apoptosis.
- To elucidate the initiating molecular event triggering widespread RNA decay in apoptosis.
- To understand the role of mitochondrial factors in apoptotic RNA decay.
Main Methods:
- Investigated RNA decay during apoptosis using knockdown and overexpression of mitochondrial proteins.
- Utilized RNase assays and structural analysis to determine PNPT1 substrate specificity.
- Examined the impact of RNA 3' end structures on decay susceptibility.
Main Results:
- Identified PNPT1, a mitochondrial exoribonuclease, as the trigger for extensive mRNA and noncoding RNA decay during apoptosis.
- PNPT1 release during MOMP initiates 3' end decay of RNAs lacking protective structures.
- Disrupting RNA 3' stem-loop structures enhances decay, while adding them confers resistance.
Conclusions:
- PNPT1 release from mitochondria during MOMP is the initiating event for apoptotic RNA decay.
- Apoptotic RNA decay preferentially targets RNAs with accessible 3' ends, such as mRNAs and poly(A) noncoding RNAs.
- RNA structural elements dictate susceptibility to PNPT1-mediated decay, highlighting a regulatory mechanism in apoptosis.
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