An interesting new paper. I guess the message is that we should take a lot of rapamycin if we’re planning to suffer from heat stroke . But it is compelling to learn that this IP injection (1mg/kg dosing) pre EHS exposure obviously got to the brain well enough to protect it.
Exertional heat stroke (EHS) causes severe central nervous system damage, with mitochondrial dysfunction and oxidative stress playing major roles. Mitophagy, regulated by the Pink1/Parkin pathway, removes damaged mitochondria. Here, we investigated the potential of rapamycin (RAPA) to reduce hypothalamic injury in rats subjected to EHS.
RAPA mitigated pathological injury and apoptosis, reduced ROS and MDA levels, and enhanced mitochondrial membrane potential. It downregulated mTOR and p62 levels, upregulated Pink1 and Parkin, increased LC3II/LC3I ratio, and promoted LC3-Tom20 and Pink1-Parkin interactions in the hypothalamic tissue of rats treated with EHS, thereby alleviating hypothalamic injury and preserving hypothalamic function.
Conclusions
The authors infer that EHS causes hypothalamic injury via mitochondrial damage, oxidative stress, and inadequate mitophagy.
Rapamycin pre-treatment mitigates hypothalamic injury in the EHS model by inhibiting mTOR, thereby activating the PINK1/Parkin-mediated mitophagy pathway, decreasing oxidative damage and preserving mitochondrial function.
They propose a mechanistic chain: EHS → mitochondrial damage/ROS → sub-optimal PINK1/Parkin activation → neuronal injury; rapamycin improves this via mTOR inhibition and up-regulating mitophagy.
They suggest possible translational relevance for central nervous system protection in EHS patients.
Novelty / Contribution
While mitophagy (via PINK1/Parkin) has been studied in many contexts (neurodegeneration, cardiac injury, ageing) the specific setting of hypothalamic injury in exertional heat stroke (EHS) is less well characterised. The study fills a gap by linking EHS-induced CNS injury to mitochondrial damage and mitophagy in the hypothalamus.
The use of rapamycin as a therapeutic pre-treatment to up-regulate mitophagy in EHS is relatively novel in this specific domain (hypothalamic injury under heat stress).
The mechanistic layering—connecting mTOR inhibition → PINK1/Parkin activation → enhanced mitophagy → reduced neuronal apoptosis/oxidative stress in the hypothalamus after EHS—is a nice integrative contribution.
For fields concerned with heat-stroke management, CNS protection, and mitochondrial quality control, this provides new experimental data and a potential target (mitophagy/mTOR).
Although rapamycin has been used widely in autophagy/mitophagy research, this particular model (EHS) and tissue (hypothalamus) is less common, so it can stimulate further work into interventions for heat-stroke brain injury.
Your comment got me digging more into this with CGPT5. Your suspicion seems correct:
Bottom line
Rapamycin (sirolimus/rapalogs): robust mechanistic plausibility to raise mitophagy tone via mTORC1 inhibition, with many preclinical reports of increased PINK1/Parkin signaling or Parkin translocation. But in humans, there’s no direct clinical proof yet that rapamycin specifically elevates PINK1/Parkin in tissues and improves hard outcomes; neurodegeneration trials are early or negative/neutral so far. (PMC)
Exercise, fasting/CR, urolithin A still have the strongest human-facing data for nudging mitophagy with functional benefits—though pathway specificity (PINK1/Parkin vs. other mitophagy routes) remains mixed. (De Gruyter Brill)
What the evidence actually says
1) Human genetics & rationale (unchanged)
Loss-of-function in PINK1 or PRKN (Parkin) causes early-onset PD and impaired mitochondrial QC—so restoring/activating this axis is attractive. Reviews synthesize the pathway’s centrality and druggability. (Nature)
2) Interventions and their relationship to PINK1/Parkin in humans
Urolithin A (UA)
Multiple RCTs in middle-aged/older adults show improved muscle strength/endurance with mitochondrial biomarkers consistent with enhanced mitophagy/biogenesis. These don’t biopsy PINK1/Parkin directly, but they’re the cleanest clinical signals that “more mitophagy” → better function. (PMC)
Exercise
Human muscle studies show exercise increases mitophagy during recovery, but dependence on PINK1/Parkin is variable (other nodes like AMPK/ULK1, BNIP3/NIX can dominate). (De Gruyter Brill)
Fasting / caloric restriction
Human-adjacent data suggest increased mitophagy markers with fasting/CR; PINK1/Parkin-specific readouts are inconsistent across tissues/timepoints. (Nature)
Rapamycin / rapalogs (NEW)
Preclinical & mechanistic: Numerous studies report that rapamycin enhances mitophagy and often up-regulates PINK1/Parkin or Parkin recruitment, across cell types and animal models (brain, muscle, kidney, eye). Examples: increased PINK1/Parkin/LC3 expression and Parkin translocation; mitophagy-dependent cognition rescue in 5xFAD mice; mitigation of mitochondrial myopathy pathology. (PMC)
Human clinical signals so far:
Neurodegeneration: A phase II sirolimus trial in multiple system atrophy (48 weeks) was futile on progression/biomarkers; pathway engagement wasn’t shown. (PubMed)
AD/aging cognition: Perspective/review pieces note ongoing or planned trials of rapamycin/everolimus with brain imaging and CSF biomarkers; no completed efficacy readouts yet. (Nature)
Broader aging endpoints: Reviews summarize rapamycin’s favorable effects on various age-associated parameters, but direct human evidence of PINK1/Parkin activation is still missing. (The Lancet)
Why the gap?
Rapamycin triggers macro-autophagy broadly; whether canonical PINK1→Parkin mitophagy is the main driver in human tissues is unresolved without target-engagement biomarkers (e.g., phospho-ubiquitin, Parkin translocation) in biopsies. State-of-the-art reviews stress the pathway’s centrality but also highlight parallel mitophagy routes that rapamycin may influence indirectly. (Nature)
3) “Direct” boosters & the road ahead (unchanged, but relevant to rapa)
Small-molecule Parkin activators (allosteric “molecular glues”) show biochemical activation and cellular rescue preclinically; human trials are pending. (Nature)
Gene therapy to increase Parkin: conceptually attractive; no completed human trials specifically up-regulating Parkin as of now. (Nature)
If your goal today is to bias biology toward better mitochondrial QC: favor exercise, consider UA, and use fasting/CR judiciously—these have the strongest human outcome data (albeit pathway-nonspecific). (PMC)
Rapamycin remains compelling mechanistically (many models show ↑PINK1/Parkin-mediated mitophagy), but human, pathway-specific evidence is currently lacking, and the only completed movement-disorder trial to date was negative on progression. If you’re using rapamycin for other indications, you should treat “PINK1/Parkin elevation” as unproven in humans pending biopsy-level target-engagement and positive clinical endpoints. (PMC)
What to watch next
Neuro trials completing in 2025–2026 that include brain imaging/CSF biomarkers under rapamycin/everolimus. (Nature)
Studies that add phospho-ubiquitin (Ser65-Ub), Parkin translocation, or mitophagy reporters in human muscle/skin biopsies after rapamycin or combined exercise ± rapamycin. Method papers and reviews keep calling for these assays. (Nature)
If you’d like, I can put together a one-pager trial watchlist (with expected readouts and the specific mitophagy biomarkers they plan to measure) and keep it current.
. But it is compelling to learn that this IP injection (1mg/kg dosing) pre EHS exposure obviously got to the brain well enough to protect it.