Discovery of a correlation between mitochondrial respiratory chain supercomplex formation in leukocytes and disease progression in patients with neurodegenerative diseases

A research group led by Associate Professor Ayako Okado-Matsumoto from the Department of Biology at Toho University, in collaboration with Professor Ryuji Sakakibara (at the time of the study) from the Department of Neurology at Toho University Medical Center Sakura Hospital, discovered that the formation of mitochondrial respiratory chain supercomplexes, encompassing energy production-related enzymes, in the peripheral blood leukocytes of patients with neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies) correlates with disease progression.

This study was made available online on November 29, 2023 and was published in Volume 175 Issue 3 of The Journal of Biochemistry on 1st March 2024.

Key Points

• By improving a previously developed low-sensitivity detection method for mitochondrial respiratory chain complex I activity, the researchers analyzed the respiratory chain supercomplex formation in leukocytes using 161 peripheral blood leukocyte samples from patients with neurodegenerative diseases. Their results revealed a correlation between mitochondrial respiratory chain supercomplex formation and disease progression (Figure).
• This study is expected to accelerate biomarker development, thereby helping elucidate cognitive and motor function-related neurodegenerative disease mechanisms and contributing to early diagnosis.

Summary

Neurodegenerative diseases are assumably caused, in part, by mitochondrial dysfunction in the central nervous system. However, tracking the corresponding dynamics has been difficult. A research group led by Associate Professor Ayako Okado-Matsumoto from the Department of Biology at Toho University and Professor Ryuji Sakakibara (at the time of the study) from the Department of Neurology at Toho University Medical Center Sakura Hospital focused on the mitochondria in peripheral blood leukocytes, which could be less invasively analyzed, and discovered that changes in respiratory chain supercomplex formation correlate with disease progression.

The researchers analyzed respiratory chain supercomplex formation using high-resolution Clear Native-Polyacrylamide Gel Electrophoresis (hrCN-PAGE), enabling three-dimensional protein structure maintenance, and an improved in-gel activity detection method developed by the research group, targeting respiratory chain complex I.

Neurodegenerative disease-induced motor and cognitive function impairments typically manifest after significant neuronal loss in the affected areas (e.g., dopaminergic neuron loss in the substantia nigra is less than 30%, as assessed by pathological and dopamine imaging studies), highlighting the need for early diagnostic methods. The findings of this study, concluding that mitochondrial function in peripheral blood leukocytes changes with the disease state, would possibly accelerate biomarker development to detect the signs of neuronal loss in the central nervous system.

Journal

The Journal of Biochemistry Online issue November 29, 2023 175, (2024), 289-298

Title：Supercomplex formation of mitochondrial respiratory chain complexes in leukocytes from patients with neurodegenerative diseases

Authors：Tsukasa Hara, Ryosuke Amagai, Ryuji Sakakibara, Ayako Okado-Matsumoto*

DOI No.：10.1093/jb/mvad100

URL：https://doi.org/10.1093/jb/mvad100