Mitochondrion-Targeting Peptides and Peptidomimetics: Recent Progress and Design Principles

Abstract

Mitochondria are multifunctional subcellular organelles whose operations encompass energy production, signal transduction, and metabolic regulation. Given their wide range of roles, they have been studied extensively as a potential therapeutic target for the treatment of various diseases, including cancer, diabetes, and neurodegenerative diseases. Mitochondrion-mediated pathways have been identified as promising targets in the context of these diseases. However, the delivery of specific probes and drugs to the mitochondria is one of the major problems that remains to be solved. Over the past decade, much effort has been devoted to developing mitochondrion-targeted delivery methods based on the membrane characteristics and the protein import machinery of mitochondria. While various methods utilizing small molecules to polymeric particles have been introduced, it is notable that many of these compounds share common structural elements and physicochemical properties for optimal selectivity and efficiency. In this Perspective, we will review the most recently developed mitochondrion-targeting peptides and peptidomimetics to outline the key aspects of structural requirements and design principles. We will also discuss successful and potential applications of mitochondrial delivery to assess opportunities and challenges in the targeting of mitochondria.

Recent Advances in Chemical Biology of Mitochondria Targeting

“…(C) Amino acid sequences of six MTSs. Image reproduced with permission, from Ref Kim et al (2020) . (D) The structure of roseltide rT1.…”

“…Cysteine-rich peptides (CRPs) are natural peptides that can be extracted from plants and have broad development opportunities ( Kim et al, 2020 ). CRPs contain multiple cysteine residues and form special disulfide bonds, the excellent rigidity and tightness of which provide metabolic stability under physiological conditions ( Figure 5D ).…”

Peptide-Assisted Nucleic Acid Delivery Systems on the Rise

“…Mitochondria have their own genome whose mutations are associated with numerous disorders, such as cancer, diabetes, neurodegenerative diseases including Parkinson's disease, and more recently infectious and autoimmune diseases [225,226]. Given the link between mitochondrial dysfunction and disease, targeting of therapeutic interventions to these subcellular organelles is of vital importance [232,233]. Efficient mitochondrial gene therapy requires nanocarriers that, once inside the cell, target mitochondria and ferry nucleic acids across the outer (OMM), as well as inner mitochondrial membrane (IMM) [234].…”

Real-time studies of plasma membrane damage trigger cell apoptosis from sulfhydryl nanoparticles to support safety assessment of nanoscale materials

“…Drug delivery such as nano particles could enter cell organ through different channels: protein import channels, permeability transition pores, mitochondrial apoptosis related channels (MACs), apoptosis-related ceramide pores, the processes will possible preparative damage to the cell organ membrane. For example, mitochondria-targeting drug delivery was considered related with depolarization of mitochondrial and this process induced therapeutic agents and antioxidants effected with cells and animals [1,2]. However, cell organ depolarization closely related with membrane structure change.…”