Low oxygen rescues the growth defect in THAP12-deficient cells, consistent with earlier work showing that hypoxia can relieve Complex I dysfunction. This nominates low-oxygen therapy as a possible treatment for THAP12-related disease.

THAP12 was recently linked to a severe recessive neurodevelopmental disorder with epilepsy. Fibroblasts from these patients show the same Complex I deficiency, suggesting the disorder is rooted in the loss of Complex I regulation. (Clinical preprint: doi.org/10.64898/202...)

Without THAP12, Complex I subunits across all three modules fell, mitochondrial respiration dropped, and cells produced less ATP. Restoring THAP12 only in the nucleus, not the cytoplasm, rescued the complex.

THAP12 controls Complex I from outside mitochondria. In the nucleus, it binds and activates the genes that build the complex, including NDUFAF3, NDUFAF4, and the iron-sulfur cluster factor BOLA3.

The team ran genome-wide CRISPR screens in human cells and stained for each of Complex I's three modules to see which genes its assembly depends on. Loss of THAP12 ranked in the top 1% for destabilizing the complex, despite not being a mitochondrial protein.

Complex I is the largest complex of the electron transport chain and the entry point for electrons that power ATP production. New work from Core Investigator Isha Jain and team identifies THAP12 as a dedicated transcription factor controlling how much Complex I a cell builds.

Thanks to all of Arc's Core Investigators, Technology Center Leaders, Science Fellows, Innovation Investigators, and Ignite Awardees for an exciting few days of science. We're already looking forward to next year!

Our 3rd Annual Investigator Retreat brought together talks on genome engineering, generative protein models, and computational biology, alongside deep dives into neurodegeneration, immunology, and metabolism.

HTRA2 also partners with CLPB, another intermembrane-space protein that causes the same disease when mutated. HTRA2 degrades protein aggregates, while CLPB pulls them apart again. Losing either destabilizes Complex I, suggesting that they act as a single quality-control system.

With Complex I impaired, mitochondria burn less oxygen, and it accumulates in the tissue, damaging oxygen-sensitive proteins. The team used those proteins as a readout and found that hypoxia both cleared excess oxygen and restored protein levels.

HTRA2 loss destabilizes Complex I, the entry point of the respiratory chain. Low oxygen restored Complex I protein levels but not its enzymatic activity, suggesting the rescue worked through a mechanism other than respiration.

Breathing continuous 11% oxygen extended median lifespan nearly threefold across two independent groups of mice. It also improved motor function and cleared neuroinflammation in the striatum, a movement-controlling region where these mice develop brain lesions.

HTRA2 is a protease in the mitochondrial intermembrane space. Its loss causes 3-methylglutaconic aciduria (3-MGA), a fatal childhood disorder. The same gene, also known as PARK13, is linked to Parkinson's and was a top hit in the team's screen for genes rescued by low oxygen.

Effective treatments for mitochondrial disease are scarce. A new paper in Nature Metabolism from Core Investigator Isha Jain and team offers one, showing that breathing low-oxygen air nearly triples lifespan in a mouse model of HTRA2 deficiency.

TET1 pairings activated a target gene for up to 50 days after effector removal. A catalytically dead TET1 mutant lost the effect, confirming DNA demethylation as the mechanism behind long-term gene activation.

Most effects returned to baseline within days of the effector being removed. The screen distinguished transient from stable effects & found that stable ones all involved DNA methylation. DNMT3A pairings drove durable silencing & TET1 pairings drove durable activation.

That potency uniquely enabled a new dual-directional CRISPRi/a system. KRAB-L3MBTL3 silences one gene while a separate activator, working in parallel, turns on a different gene in the same cell.

COMBINE recruits each pair to an endogenous gene in human cells to measure its influence on gene expression. It accommodates effectors up to 2,094 amino acids (previous screens were limited to ~80-amino-acid fragments), enabling testing of full-length catalytic domains.

Cells control gene expression through combinatorial interactions between readers, writers, and erasers of chromatin marks, but most epigenetic editing tools rely on a single effector in isolation. COMBINE is the first platform to test those combinations at scale, screening 50,000+ effector pairs.

Start assembling your team because the 2026 Virtual Cell Challenge officially kicks off on Thursday, August 20. This is round two of our global competition to understand and predict how cells respond to internal cues and external stimuli.

As macrophages, SAMs should clear the tumor, but high CD36 loads them with lipids that blunt that ability. Genetic and drug blocks of the pathway, including the clinical C5aR inhibitor avacopan, reduced SAMs and extended survival in stressed mice.

In mice, chronic stress sped glioma growth and shortened survival across three tumor models. It promoted ADRB2+ bone marrow monocytes to differentiate into C5aR1+ stress-associated macrophages (SAMs) that travel from the marrow into the tumor.

Science Fellow Jingtian Zhou and colleagues traced stress-driven glioma growth in mice to a bone marrow-derived macrophage that infiltrates the brain tumor and acts on the immune environment rather than the tumor cells.

cGAMP and arginine bind separate sites on SLC7A1. The team mutated cGAMP sites without affecting arginine transport, and found that excess arginine alone protects T cells from STING-agonist death.

When T cells activate and proliferate, they upregulate SLC7A1 about 30-fold to take up arginine. That increase also lets cGAMP in, making activated T cells more vulnerable than resting ones. SLC7A1 drives over half of cGAMP-induced STING signaling and death in primary T cells.

To identify transporters, the team ran a genome-wide CRISPR screen for cGAMP survival in Jurkat T cells. The top hit was SLC7A1, a cationic amino acid transporter that imports arginine but had not previously been linked to cGAMP.

STING agonists are cGAMP and its analogs, so blocking their entry would spare T cells without depleting cGAMP elsewhere. Transporters that import cGAMP in other cell types are not the ones at work in T cells, indicating a different transporter is responsible.

STING agonists can shrink tumors and make them visible to the immune system, but high doses become toxic to T cells. Core Investigator @lingyinli.bsky.social and team have identified SLC7A1, the T cell arginine transporter, as the primary route by which these agonists enter and kill T cells

Proto also works with AI coding agents that write programs from natural language instructions. The team used this to specify hundreds of protein complexes across the human proteome, a multi-step signaling pathway, and a cancer-targeting lentiviral therapy.

To generate promoter-repressor pairs, Proto’s pipeline composed general-purpose generative and structural models to solve for both protein-protein and protein-DNA interactions simultaneously.