A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain
Francisca Diaz1, Sofia Garcia, Kyle R Padgett
1Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA. fdiaz1@med.miami.edu
Abstract:
We have created two neuron-specific mouse models of mitochondrial electron transport chain deficiencies involving defects in complex III (CIII) or complex IV (CIV). These conditional knockouts (cKOs) were created by ablation of the genes coding for the Rieske iron-sulfur protein (RISP) and COX10, respectively. RISP is one of the catalytic subunits of CIII and COX10 is an assembly factor indispensable for the maturation of Cox1, one of the catalytic subunits of CIV. Although the rates of gene deletion, protein loss and complex dysfunction were similar, the RISP cKO survived 3.5 months of age, whereas the COX10 cKO survived for 10-12 months. The RISP cKO had a sudden death, with minimal behavioral changes. In contrast, the COX10 cKO showed a distinctive behavioral phenotype with onset at 4 months of age followed by a slower but progressive neurodegeneration. Curiously, the piriform and somatosensory cortices were more vulnerable to the CIII defect whereas cingulate cortex and to a less extent piriform cortex were affected preferentially by the CIV defect. In addition, the CIII model showed severe and early reactive oxygen species damage, a feature not observed until very late in the pathology of the CIV model. These findings illustrate how specific respiratory chain defects have distinct molecular mechanisms, leading to distinct pathologies, akin to the clinical heterogeneity observed in patients with mitochondrial diseases.
Insights
Mitochondrial electron transport chain defects in mice show distinct neurodegenerative patterns. Complex III deficiency caused sudden death, while Complex IV deficiency led to progressive neurodegeneration and distinct brain region vulnerability.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Mitochondrial electron transport chain (ETC) complexes are crucial for cellular respiration.
- Defects in ETC complexes are implicated in various neurodegenerative diseases.
- Understanding the specific impact of individual complex deficiencies is vital for disease modeling.
Purpose of the Study:
- To create and characterize neuron-specific mouse models of mitochondrial Complex III (CIII) and Complex IV (CIV) deficiencies.
- To investigate the distinct pathological outcomes and neurodegenerative mechanisms resulting from CIII versus CIV defects.
- To compare the survival rates, behavioral phenotypes, and neuropathological features of these models.
Main Methods:
- Generation of conditional knockout (cKO) mice by ablating genes for Rieske iron-sulfur protein (RISP) in CIII and COX10 in CIV.
- Assessment of gene deletion, protein loss, and complex dysfunction.
- Monitoring survival rates, behavioral changes, and neurodegeneration progression.
- Analysis of regional brain vulnerability and reactive oxygen species (ROS) damage.
Main Results:
- Both RISP (CIII) and COX10 (CIV) cKOs exhibited similar rates of gene deletion and complex dysfunction.
- RISP cKO mice had a shorter survival (3.5 months) with sudden death and minimal behavioral changes.
- COX10 cKO mice survived longer (10-12 months) with progressive neurodegeneration and distinct behavioral phenotypes.
- CIII deficiency preferentially affected piriform and somatosensory cortices with early ROS damage.
- CIV deficiency preferentially affected cingulate cortex with later onset of ROS damage.
Conclusions:
- Neuron-specific defects in CIII and CIV lead to distinct neurodegenerative pathologies and survival outcomes.
- The specific ETC complex affected dictates the pattern of neurodegeneration, regional vulnerability, and associated molecular damage.
- These models recapitulate the clinical heterogeneity observed in human mitochondrial diseases, offering valuable tools for research.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:43Electron Transport Chain: Complex III and IV
01:41The Supercomplexes in the Crista Membrane
01:30The Electron Transport Chain
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
01:45Mitochondrial Membranes
01:28The Inner Mitochondrial Membrane