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Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Mitochondrial complex I is deficient in renal oncocytomas
Helene Simonnet1, Jocelyne Demont, Kathy Pfeiffer
1CGMC (Center of Molecular and Cell Genetics), Unit 5534 of the CNRS and the University Lyon 1 Claude Bernard, Villeurbanne, France. simonnet@univ-lyon1.fr
Abstract:
Renal oncocytomas are benign tumors characterized by dense accumulation of mitochondria the cause of which remains unknown so far. Consistently, mitochondrial DNA content and the amounts and catalytic activities of several oxidative phosphorylation (OXPHOS) complexes were known to be increased in these tumors, but it was not ascertained that the OXPHOS system was functional. Here we investigated mitochondrial complex I and found that its NADH dehydrogenase activity and protein content were specifically decreased in oncocytomas, in stark contrast with the parallel decrease of all respiratory chain complexes in other, malignant, renal tumors. We conclude that deficiency of complex I in oncocytomas might be the early event causing the increased mitochondrial biogenesis, attempting to compensate for the loss of OXPHOS function. Since other tumors were found to be linked to mitochondrial deficiencies like genetic alterations of fumarate hydratase or succinate dehydrogenase, oncocytoma could be the third type of benign tumor associated with impairment of mitochondrial ATP production in an oxidative, quiescent tissue. Besides, complex I enzyme activity was moderately decreased in the vicinity of oncocytomas, when compared with normal tissue adjacent to other renal tumors. This suggested that oncocytomas are the result of at least two serial modifications altering the mitochondrial respiratory chain.
Insights
Renal oncocytomas show a specific decrease in mitochondrial complex I, unlike malignant tumors. This deficiency may drive increased mitochondria and impaired ATP production in these benign kidney tumors.
Area of Science:
- Nephrology
- Mitochondrial Biology
- Oncology
Background:
- Renal oncocytomas are benign tumors with increased mitochondria, but the functionality of their oxidative phosphorylation (OXPHOS) system is unclear.
- Previous studies noted increased mitochondrial DNA and OXPHOS complex activity, yet functional assessment was lacking.
Purpose of the Study:
- To investigate the functional status of mitochondrial complex I in renal oncocytomas.
- To differentiate mitochondrial alterations in oncocytomas from those in malignant renal tumors.
Main Methods:
- Analysis of NADH dehydrogenase activity and protein content of mitochondrial complex I in oncocytomas.
- Comparison of complex I alterations in oncocytomas with those in malignant renal tumors.
- Assessment of complex I activity in peritumoral tissue.
Main Results:
- Renal oncocytomas exhibit a specific decrease in mitochondrial complex I (NADH dehydrogenase) activity and protein content.
- In contrast, malignant renal tumors show a parallel decrease in all respiratory chain complexes.
- Complex I activity is also moderately reduced in tissue adjacent to oncocytomas.
Conclusions:
- Complex I deficiency is a potential early event in oncocytoma development, triggering compensatory mitochondrial biogenesis.
- Oncocytoma represents a third type of benign tumor linked to impaired mitochondrial ATP production.
- The findings suggest oncocytomas arise from at least two sequential alterations affecting the mitochondrial respiratory chain.
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