bims-mitpro 2025-01-19 papers

Issue of 2025–01–19
five papers selected by
Andreas Kohler, Umeå University

Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]

Reacting to reductive stress at the mitochondrial import gate.

A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.

Keywords: TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin

DOI: https://doi.org/10.1016/j.tcb.2024.12.013

FEBS Open Bio. 2025 Jan 16.

FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production.

Yushi Otsuka, Masato Yano.

FAM136A deficiency has been associated with Ménière's disease. However, the underlying mechanism of action of this protein remains unclear. We hypothesized that FAM136A functions in maintaining mitochondria, even in HepG2 cells. To better characterize FAM136A function, we analyzed the cellular response caused by its depletion. FAM136A depletion induced reactive oxygen species (ROS) and reduced both mitochondrial membrane potential and ATP production. However, cleaved caspase-9 levels did not increase significantly. We next investigated why the depletion of FAM136A reduced the mitochondrial membrane potential and ATP production but did not lead to apoptosis. Depletion of FAM136A induced the mitochondrial unfolded protein response (UPRmt) and the expression levels of gluconeogenic phosphoenolpyruvate carboxykinases (PCK1 and PCK2) and ketogenic 3-hydroxy-3-methylglutaryl-CoA synthases (HMGCS1 and HMGCS2) were upregulated. Furthermore, depletion of FAM136A reduced accumulation of holocytochrome c synthase (HCCS), a FAM136A interacting enzyme that combines heme to apocytochrome c to produce holocytochrome c. Notably, the amount of heme in cytochrome c did not change significantly with FAM136A depletion, although the amount of total cytochrome c protein increased significantly. This observation suggests that greater amounts of cytochrome c remain unbound to heme in FAM136A-depleted cells.

Keywords: ATP; FAM136A; holocytochrome c synthetase; mitochondrial membrane potential; mitochondrial stress

DOI: https://doi.org/10.1002/2211-5463.13967

Int J Biol Macromol. 2025 Jan 08. pii: S0141-8130(25)00200-4. [Epub ahead of print] 139651

Alcohol dehydrogenase 1 acts as a scaffold protein in mitophagy essential for fungal pathogen adaptation to hypoxic niches within hosts.

Jin-Li Ding, Li Li, Kang Wei, Hao Zhang, Nemat O Keyhani, Ming-Guang Feng, Sheng-Hua Ying.

Fungi have evolved diverse physiological adaptations to hypoxic environments. However, the mechanisms mediating such adaptations remain obscure for many filamentous pathogenic fungi. Here, we show that autophagy mediated mitophagy occurs in the insect pathogenic fungus Beauveria bassiana under hypoxic conditions induced by host cellular immune responses. Mitophagy was essential for fungal evasion from insect hemocyte encapsulation, allowing for fungal proliferation and colonization in the host hemocoel. Our data showed that B. bassiana autophagy-related protein 11 (Atg11) interacts with Atg8 as a scaffold mediating mitophagy. The mitochondrial protein Atg43 was demonstrated to act as a receptor for the selective mitophagy, directly interacting with Atg8 for the autophagosomal targeting. Alcohol dehydrogenase BbAdh1, as a novel scaffold protein, participates in mitophagy through interacting with Atg8 and Atg11 under hypoxic stress. BbAdh1 was critical for fungal intracellular redox homeostasis and energy metabolism under hypoxic conditions. These data provide a pathway for mitochondrial degradation via metabolism linked autophagosome- to-vacuole targeting during hypoxic stress. This mitophagy results in depletion of oxidative mitochondrial dependent functions as a cellular adaptation to the low oxygen levels.

Keywords: Fungal survival; Hypoxic stress; Mitophagy

DOI: https://doi.org/10.1016/j.ijbiomac.2025.139651

EMBO J. 2025 Jan 13.

NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism.

Chris A Brosey, Runze Shen, John A Tainer.

Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates. NMR and X-ray scattering (SAXS) solution measurements, mutational analyses, and biochemistry show that the substrate-mimicking AIF-interaction domain shields CHCHD4's redox-sensitive active site. Disrupting this shield critically activates CHCHD4 substrate affinity and chaperone activity. Regulatory-domain sequestration by NADH-activated AIF directly stimulates chaperone binding and folding, revealing how AIF mediates CHCHD4 mitochondrial import. These results establish AIF as an integral component of the metazoan disulfide relay and point to NADH-activated dimeric AIF as an organizational import center for CHCHD4 and its substrates. Importantly, AIF regulation of CHCHD4 directly links AIF's cellular NAD(H) sensing to CHCHD4 chaperone function, suggesting a mechanism to balance tissue-specific oxidative phosphorylation (OXPHOS) capacity with NADH availability.

Keywords: Apoptosis-inducing Factor (AIF); CHCHD4/MIA40; OXPHOS; Small-angle X-ray Scattering (SAXS); X-ray Crystallography

DOI: https://doi.org/10.1038/s44318-024-00360-6