Biology subjects

Challis, M. P.

Publications and source records attributed to Challis, M. P..

3 recordsLinked to original sources

bioRxiv2026

Proximity labelling of the BAK macropore uncovers a new role for SLC35A4-MP in mitochondrial dynamics

Mitochondrial permeabilization by the apoptotic executioners BAK and BAX represents a critical stage of mitochondrial apoptosis and facilitates the release of pro-inflammatory mitochondrial DNA via herniation of the inner mitochondrial membrane. This study utilises TurboID proximity labelling to investigate the temporal changes of the BAK proximal proteome during mitochondrial herniation and apoptosis. In doing so, we detail a comprehensive BAK proximal proteome, both at steady state and during apoptosis and observe the loss of MICOS complex stability and proximity to the BAK pore as apoptosis proceeds. In addition, we identify the mitochondrial microprotein SLC35A4-MP proximal to the BAK pore and reveal a SLC35A4-MP dependent modulation of OPA1 processing. Furthermore, loss of SLC35A4-MP delays mitochondrial fragmentation in response to a variety of stressors, uncovering a previously unrecognised role for SLC35A4-MP in fine-tuning mitochondrial rearrangement during apoptotic stress.

cell biology↗

bioRxiv2026

Characterization of human Metaxin proteins reveals functional diversification of SAM37 homologs MTX1 and MTX3

The biogenesis of outer mitochondrial membrane {beta}-barrel proteins relies on the mitochondrial Sorting and Assembly Machinery (SAM) complex. In humans, the SAM complex contains SAM50 along with Metaxin (MTX) accessory subunits. MTX1 and MTX3 are homologous yet their functional similarities and differences have scarcely been investigated. Homozygous null mutations in the MTX2 gene are linked to a rare progeroid syndrome that causes severe depletion of MTX1. Here, we uncover unique phenotypes associated with the loss of MTX1 or MTX3 in human cells. Loss of MTX1 confers a deficiency in mitochondrial volume and causes network-wide mitochondrial morphology abnormalities. MTX3 loss resulted in negligible consequences for the biogenesis of {beta}-barrel proteins but resulted in increased mitochondrial mass. We also find that both MTX1 and MTX3 stability are dependent on the presence of MTX2, with MTX1 deficiency causing defective import and assembly. Collectively, our findings support the notion that MTX1 and MTX3 are functionally diverse homologs and are unlikely to be functionally redundant.

biochemistry↗

bioRxiv2025

PfK13-associated artemisinin resistance slows drug activation and enhances antioxidant defence, which can be overcome with sulforaphane.

Artemisinin resistance is globally prevalent, including in Africa, raising concerns and highlighting the need to better understand the cellular mechanisms behind this resistance. In Plasmodium falciparum, artemisinin resistance is primarily attributed to mutations in the PfKelch13 (PfK13) gene. In this study, we performed proteomic analysis on a range of sensitive and artemisinin-resistant parasites (both laboratory-generated and field isolates), revealing specific dysregulation of PfK13 protein abundance. Reduced PfK13 levels were linked to impaired hemoglobin digestion, decreased free heme levels, and consequently, decreased artemisinin activation. Artemisinin resistant parasites also exhibited elevated thiol levels, indicating a more reduced cellular state. Targeting the parasite redox capacity with sulforaphane potentiated artemisinin activity in vitro and in an in vivo rodent Plasmodium berghei model, offering a potential strategy to overcome resistance. Our findings provide critical insights into the molecular mechanisms of artemisinin resistance and suggest novel therapeutic interventions to restore drug sensitivity. One Sentence Summary: PfK13 mutations drive artemisinin resistance in Plasmodium parasites by enhancing antioxidant defences, which can be targeted by redox modulators such as sulforaphane.

microbiology↗