Optical Imaging Demonstrates Tissue-Specific Metabolic Perturbations in Mblac1 Knockout Mice

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• Metabolic alterations are common in neurodegenerative diseases like Parkinson's and Alzheimer's disease (AD).
• Mutations in C. elegans swip-10 cause motor dysfunction and neuron degeneration.
• The human ortholog MBLAC1 is an AD risk factor, particularly in individuals with cardiovascular issues, suggesting broader metabolic impacts.

Purpose of the Study:

• To investigate if MBLAC1 deficiency affects mitochondrial respiration in peripheral tissues.
• To quantify mitochondrial coenzyme levels and redox ratio in MBLAC1 knockout (KO) mice.
• To correlate MBLAC1 expression with metabolic changes and potential comorbidities.

Main Methods:

• Utilized Mblac1 knockout (KO) mice and wild-type (WT) littermates.
• Quantified NADH, FAD, and NADH/FAD redox ratio (RR) in liver and kidney tissues using 3D optical cryo-imaging.
• Analyzed serum glucose and cholesterol levels.

Main Results:

• MBLAC1 KO mice showed significantly reduced liver RR, primarily due to lower NADH levels, with no sex differences.
• No significant genotype or sex differences were observed in kidney tissues.
• KO mice exhibited elevated serum glucose and diminished cholesterol in aged individuals, indicating liver dysfunction.

Conclusions:

• MBLAC1 deficiency leads to metabolic changes in peripheral organs, not just neural cells.
• These findings align with peripheral comorbidities observed in neurodegenerative diseases linked to MBLAC1.
• Reduced MBLAC1 protein expression may contribute to a broader metabolic insult impacting disease risk.