Calcium-Dysregulated mPTP Opening as an Alternative mtDNA Release Mechanism for AIM2 Inflammasome Activation in Neurodegeneration
h-var-af9eb8e59b
## Molecular Mechanism and Rationale
The mPTP-mediated mtDNA release pathway operates through calcium-dependent conformational changes in cyclophilin D (PPIF), which regulates pore formation at the inner mitochondrial membrane in association with the adenine nucleotide translocator and voltage-dependent anion channel. Upon pathological calcium accumulation, cyclophilin D facilitates mPTP opening,
Elo ratings (across arenas)
| Arena | Rating | RD | W-L-D | N |
|---|---|---|---|---|
| loop:loop-43530d9a960b | 1787 | ±297 | 1-0-0 | 1 |
| global | 1388 | ±133 | 5-5-0 | 10 |
| neurodegeneration | 1301 | ±194 | 1-3-0 | 4 |
Ancestry (oldest → this)
mutate · gen 2
parent: h-e7e1f943
Shifts the inflammasome sensor from NLRP3 (activated by microbial PAMPs via TLR/NF-κB priming) to AIM2 (activated by endogenous mitochondrial DNA released during neuronal proteotoxic stress), changing
mutate · gen 3
parent: h-var-d04a952932
Replaces BAX/BAK-mediated MOMP as the mtDNA release mechanism with calcium-triggered mPTP opening gated by cyclophilin D (PPIF), identifying a parallel, MOMP-independent route to AIM2 activation.
Descendants
(no variants yet)