Cyclohexylalanine-Containing α-Helical Amphipathic Peptide Targets Cardiolipin, Rescuing Mitochondrial Dysfunction in Kidney Injury

Abstract

Mitochondrial dysfunction is linked to degenerative diseases, resulting from cardiolipin (CL)-induced disruption of cristae structure in the inner mitochondrial membrane (IMM); therefore, preserving cristae and preventing CL remodeling offer effective strategies to maintain mitochondrial function. To identify reactive oxygen species (ROS)-blocking agents against mitochondrial dysfunction, a library of cyclohexylamine-containing cell-penetrating αhelical amphipathic "bundle" peptides were screened. Among these, CMP3013 is selectively bound to abnormal mitochondria, preserving the cristae structure impaired by mitochondriadamaging agents. With a stronger affinity for CL compared with other IMM lipid components, CMP3013 exhibited high selectivity. Consequently, it protected cristae, reduced ROS production, and enhanced adenosine triphosphate (ATP) generation. In mouse models of acute kidney injury, a 1 mg/kg dose of CMP3013 demonstrated remarkable efficacy, highlighting its potential as a therapeutic agent for mitochondrial dysfunction-related disorders. Overall, CMP3013 represents a promising agent for mitigating mitochondrial dysfunction and associated diseases.

The Role of Cardiolipin in Mitochondrial Function and Neurodegenerative Diseases

“…For instance, the synthetic CMP3013, a cyclohexylalanine-containing α-helical amphipathic peptide, has been demonstrated as a protective agent preserving the mitochondrial cristae structure and enhancing ATP production in models of kidney dysfunction. CMP3013 exhibits high selectivity for CL compared to other IMM lipid components [128]. Remarkably, the pharmacologic inhibition of CL alterations with XJB-5-131, a synthetic mitochondria-targeted electron and reactive oxygen species scavenger, attenuated cell death and tissue damage, and ameliorated motor deficits after SCI in adult rats [93,129].…”