FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production
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...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-05-01
|
| Series: | FEBS Open Bio |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/2211-5463.13967 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849720220898295808 |
|---|---|
| author | Yushi Otsuka Masato Yano |
| author_facet | Yushi Otsuka Masato Yano |
| author_sort | Yushi Otsuka |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e1e7c3f78e884eb9b1c06341db5c4ad6 |
| institution | DOAJ |
| issn | 2211-5463 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj-art-e1e7c3f78e884eb9b1c06341db5c4ad62025-08-20T03:11:58ZengWileyFEBS Open Bio2211-54632025-05-0115573875310.1002/2211-5463.13967FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP productionYushi Otsuka0Masato Yano1Department of Medical Technology, Faculty of Health Sciences Kumamoto Health Science University Kumamoto JapanDepartment of Medical Technology, Faculty of Health Sciences Kumamoto Health Science University Kumamoto JapanFAM136A 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.https://doi.org/10.1002/2211-5463.13967ATPFAM136Aholocytochrome c synthetasemitochondrial membrane potentialmitochondrial stress |
| spellingShingle | Yushi Otsuka Masato Yano FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production FEBS Open Bio ATP FAM136A holocytochrome c synthetase mitochondrial membrane potential mitochondrial stress |
| title | FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production |
| title_full | FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production |
| title_fullStr | FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production |
| title_full_unstemmed | FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production |
| title_short | FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production |
| title_sort | fam136a depletion induces mitochondrial stress and reduces mitochondrial membrane potential and atp production |
| topic | ATP FAM136A holocytochrome c synthetase mitochondrial membrane potential mitochondrial stress |
| url | https://doi.org/10.1002/2211-5463.13967 |
| work_keys_str_mv | AT yushiotsuka fam136adepletioninducesmitochondrialstressandreducesmitochondrialmembranepotentialandatpproduction AT masatoyano fam136adepletioninducesmitochondrialstressandreducesmitochondrialmembranepotentialandatpproduction |