FAM136A is an essential chaperone for mitochondrial membrane protein biogenesis

Verdict. ABSTRACT The metabolic and signaling function of mitochondria rely on a network of chaperones within the inner membrane space (IMS) that regulate the biogenesis of nascent mitochondrial proteins. It intersects mitochondrial stress/dysfunction themes (OXPHOS / ETC; systemic metabolic stress).

What the authors report

FAM136A is a ubiquitously expressed essential gene, that is conserved in metazoa and plants. FAM136A also binds and chaperones a subset of α-helical subunits of the electron transport chain.

Key results stated in the abstract include the following. ABSTRACT The metabolic and signaling function of mitochondria rely on a network of chaperones within the inner membrane space (IMS) that regulate the biogenesis of nascent mitochondrial proteins. Using a genome wide CRISPRi screen we found that in human cells FAM136A is required for biogenesis of all three voltage-dependent anion channel (VDAC) paralogs, an abundant and essential family of β-barrel metabolite transporters in the outer mitochondrial membrane (OM). Using a combination of experiments in human cells and in vitro reconstitution, we determined that FAM136A associates with unfolded VDACs in the IMS; solubilizes nascent VDAC through a direct interaction; and facilitates insertion of VDAC into the OM.

Why it matters for mitochondrial biology

Within mitochondrial research, this work maps primarily to OXPHOS, biogenesis, metabolism, genetics. It is relevant to mitochondrial dysfunction discourse because the abstract invokes OXPHOS / ETC, systemic metabolic stress. That does not by itself establish a validated disease mechanism; it indicates thematic proximity. OXPHOS/ETC involvement, if confirmed, would place the work in the core of bioenergetic pathophysiology rather than peripheral organelle biology. Causal language appears in the abstract; such claims should be treated as provisional until design details (loss-of-function, rescue, dose-response) are verified. Server: biorxiv. Posted 2026-08-04. Synthesis confidence is bounded by abstract completeness.

Study design (abstract-level)

Using a genome wide CRISPRi screen we found that in human cells FAM136A is required for biogenesis of all three voltage-dependent anion channel (VDAC) paralogs, an abundant and essential family of β-barrel metabolite transporters in the outer mitochondrial membrane (OM). Using a combination of experiments in human cells and in vitro reconstitution, we determined that FAM136A associates with unfolded VDACs in the IMS; solubilizes nascent VDAC through a direct interaction; and facilitates insertion of VDAC into the OM.

Principal findings

1. ABSTRACT The metabolic and signaling function of mitochondria rely on a network of chaperones within the inner membrane space (IMS) that regulate the biogenesis of nascent mitochondrial proteins.
2. Using a genome wide CRISPRi screen we found that in human cells FAM136A is required for biogenesis of all three voltage-dependent anion channel (VDAC) paralogs, an abundant and essential family of β-barrel metabolite transporters in the outer mitochondrial membrane (OM).
3. Using a combination of experiments in human cells and in vitro reconstitution, we determined that FAM136A associates with unfolded VDACs in the IMS; solubilizes nascent VDAC through a direct interaction; and facilitates insertion of VDAC into the OM.
4. We therefore conclude that FAM136A is an IMS-resident chaperone, necessary and sufficient to maintain nascent membrane proteins in a folding-competent state to mediate their integration into the bilayer.

Limitations of this brief

• This Mitos brief is an abstract-level synthesis of a preprint; it is not peer review and not a substitute for reading the full paper.
• Preprint status: findings may change with revision or journal review.
• Effect sizes, n numbers, statistics, and full experimental controls are typically incomplete at abstract resolution.
• Comparator/control language is weak or absent in the abstract, limiting causal inference from this brief alone.
• Primary source: biorxiv DOI 10.64898/2026.08.03.742567 (posted 2026-08-04).

Open scientific questions

• Which specific experimental panels in the full paper establish the strongest causal claim, and how robust are the controls?
• Are OXPHOS defects primary drivers or secondary consequences of broader cellular stress?
• How do these findings sit relative to prior literature on the same pathway—replication, contradiction, or incremental extension?

Bottom line

For mitochondrial biologists focused on OXPHOS, biogenesis, metabolism, this preprint is worth full-text review soon. Abstract-level takeaway: ABSTRACT The metabolic and signaling function of mitochondria rely on a network of chaperones within the inner membrane space (IMS) that regulate the biogenesis of nascent mitochondrial proteins. Confirm methods, effect sizes, and controls in the full PDF before citing the result as established.

Bibliographic record

Abstract-based editorial synthesis by Mitos. Not peer review.