Power of mitochondrial drug delivery systems to produce innovative nanomedicines

https://doi.org/10.1016/j.addr.2020.09.010Get rights and content

Abstract

Mitochondria carry out various essential functions including ATP production, the regulation of apoptosis and possess their own genome (mtDNA). Delivering target molecules to this organelle, it would make it possible to control the functions of cells and living organisms and would allow us to develop a better understanding of life. Given the fact that mitochondrial dysfunction has been implicated in a variety of human disorders, delivering therapeutic molecules to mitochondria for the treatment of these diseases is an important issue. To date, several mitochondrial drug delivery system (DDS) developments have been reported, but a generalized DDS leading to therapy that exclusively targets mitochondria has not been established. This review focuses on mitochondria-targeted therapeutic strategies including antioxidant therapy, cancer therapy, mitochondrial gene therapy and cell transplantation therapy based on mitochondrial DDS. A particular focus is on nanocarriers for mitochondrial delivery with the goal of achieving mitochondria-targeting therapy. We hope that this review will stimulate the accelerated development of mitochondrial DDS.

Introduction

Mitochondria carry out vital and lethal functions for cells that are relevant to the pathophysiology of diseases. Mitochondria are responsible for providing a significant portion of cellular energy in the form of adenosine triphosphate (ATP), for controlling the level of reactive oxygen species (ROS), buffering cytosolic calcium levels, and regulating programmed cell death (apoptosis) [1]. To support their functions, mitochondria are supplied by several proteins that are encoded either by mitochondrial DNA (mtDNA) or nuclear DNA. Fig. 1 is shown to summarize our current understanding of mitochondrial structure and their various functions [2]. The mitochondrion possesses a double membrane consisting of an outer membrane, which includes important proteins related to apoptosis regulation, and an inner membrane containing the mitochondrial oxidative phosphorylation system, including proteins related to the electron transport chain and ATP synthase. The very inner space, the matrix, contains pooled mtDNA and major metabolic pathways, including the tricarboxylic acid (TCA) cycle, the urea cycle and fatty acid oxidation (β-oxidation). Thus, by delivering target molecules to mitochondria, it would be possible, in theory, to control the functions of cells and living organisms, which could be useful for our fundamental understanding of life phenomena.

It has often been reported that mitochondrial dysfunction can cause a variety of human disorders, including neurodegenerative and neuromuscular diseases, heart failure, ischemia/reperfusion (I/R) injuries, cancer and a variety of inherited mitochondrial diseases [[3], [4], [5], [6]]. For example, inherited mitochondrial diseases are caused by mutations and defects of mtDNA. Thus, if it were possible to deliver therapeutic compounds to the mitochondrial matrix where the mtDNA is located, the condition caused by such mutations and defects of mtDNA in mitochondria in diseased cells could be improved. While, the mitochondrial delivery of compounds that are toxic to mitochondria and destroy them, the energy plant of cancer cells could be destroyed. Such a mitochondrial targeting strategy would be useful for cancer therapy [7].

Based on the above information, mitochondria would be expected to be promising organelles for targeting. The technology of delivering the target molecule to mitochondria should have a substantial impact on our understanding of life processes. Moreover, delivering therapeutic molecules to mitochondria for the treatment of a variety of human disorders promises to be a useful innovative therapeutic strategy. It should be noted here that the transport system of naïve mitochondria is strictly controlled as shown in Fig. 2 [2]. The outer membrane is only permeable to small molecules with molecular weights of less than 5 kDa, with passage through a membrane-spanning protein, namely porin. Macromolecules, such as proteins, are taken up by mitochondria via a protein transport machinery by a special route. The mitochondrial protein import machinery is involved in mitochondrial transport of a variety of proteins linked with mitochondrial targeting signal peptide (MTS). Specific compounds reach the matrix space via a number of transport proteins that are imbedded within the inner membrane—each of which is responsible for the transport of a specific ligand.

For the treatment of a mitochondrial disease, the molecular mechanism and pathway of mitochondrial diseases needs to be elucidated and a drug delivery system (DDS) for mitochondria in diseased cells is required. First, methodology for encapsulating drugs in nanocarriers independent of the physicochemical characteristics of the drugs are needed. Second, the nanocarriers should be internalized into the target cells of a diseased tissue. Finally, the precise control of the intracellular trafficking of a nanocarrier is required to deliver the cargo to the mitochondria. Therefore, the development of DDS technology for delivering cargoes to mitochondrial sites, irrespective of the size and type of molecule, would be highly desirable. To date, several mitochondrial DDS developments have been reported [2,8,9], but a generalized DDS leading to therapy targeting mitochondria has not been established. The mitochondrial delivery of macromolecules such as nucleic acids and proteins is particularly difficult using the currently available technology for targeting mitochondria.

This review focuses on mitochondria-targeted therapeutic strategies including antioxidant therapy, cancer therapy, mitochondrial gene therapy and cell transplantation therapy based on mitochondrial DDS. In particular, we discuss nanocarriers for mitochondrial delivery to achieve mitochondria-targeting therapy. In the section on antioxidant therapy targeting mitochondria, we summarize the current state of knowledge of mitochondrial delivery of anti-oxidant molecules, including chemicals, peptides. The discussion of cancer therapy includes the mitochondrial delivery of anticancer drugs and mitochondrial targeted photodynamic therapy (PDT). In the section of mitochondrial gene therapy, we summarize current therapeutic methods that are available for the treatment of mitochondrial inherited diseases and discuss the mitochondrial delivery of small nucleic acids and circular DNA for an innovative mitochondrial gene therapy. Finally, we introduce cell plantation therapy using mitochondria activated cells. This review also summarizes our current efforts regarding a liposome-based carrier for mitochondrial delivery, MITO-Porter that delivers cargoes to mitochondria via a membrane fusion mechanism.

Section snippets

Antioxidant therapy using mitochondrial DDS

In this section, research related to antioxidant therapy targeting mitochondria is described. Current reports of the use of mitochondrial DDS in antioxidant therapy are mainly classified into three groups: mitochondrial delivery via triphenylphosphonium (TPP), Szeto-Schiller (SS)-peptides, and mitochondrial targeting nanocarriers (Fig. 3).

Cancer therapy targeting mitochondria

In the early 19th century, a German physiologist and Nobel laureate, Otto Heinrich Warburg hypothesized the existence of a close relationship between defects in mitochondrial function with tumorigenesis [53]. He observed that tumors rely on aerobic glycolysis, even in an oxygen-rich environment, by taking up more glucose and secreting increased levels of lactate to the tumor microenvironment (termed the Warburg effect). In current studies, Chandel et al. proposed that aerobic glycolysis is

Mitochondrial diseases and an attempt toward mitochondrial gene therapy

Mitochondrial diseases are defined as a group of genetic disorders that are characterized by defects in oxidative phosphorylation, which are caused by genetic mutations in the both the mtDNA and nuclear DNA that encode mitochondrial proteins or proteins that are related to mitochondrial function [129]. Mitochondrial diseases have wide heterogeneities and can occur at any age, resulting in various manifestations with a broad range of clinical phenotypes [129]. Mitochondrial diseases can occur in

Cell transplantation therapy and mitochondrial activation

The use of stem cell therapy for the treatment of mitochondrial diseases has been reported [196]. Hematopoietic stem cell transplantation therapy to maintain thymidine phosphorylase activity was found to lower the levels of thymidine and deoxyuridine in patient's blood and lead to improvements in the clinical symptoms in the patients suffering from the MNGIE syndrome. Unfortunately, more than 50% therapy-related deaths have been reported [196]. Cell transplantation therapy and the relationship

Conclusions

Research on mitochondria with various functions have been carried out around the world for a long time, and controlling the functions of this organelle is expected to be studied deeply in attempts to understand the life sciences and develop innovative therapeutic strategies. To achieve such an innovative research and mitochondrial therapy, a mitochondrial DDS will be required. At the beginning of the 2000s, when we started our own research to develop a mitochondrial DDS, there were only a few

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgements

This research was funded by Grants-in-Aid for Scientific Research (B) (17H02094 to Y.Y.) from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government (MEXT), a grant from the Special Education and Research Expenses of the MEXT, a grant from the Uehara Memorial Foundation (to Y.Y.), a grant from the KOSE Cosmetology Research Foundation (to Y.Y.) and a grant from the Takeda Science Foundation (to Y.Y.). We wish to thank Dr. Milton Feather for his helpful advice

References (213)

  • T.M. Brenza et al.

    Neuronal protection against oxidative insult by polyanhydride nanoparticle-based mitochondria-targeted antioxidant therapy

    Nanomedicine

    (2017)
  • M. Wu et al.

    Liver-targeted Nano-MitoPBN normalizes glucose metabolism by improving mitochondrial redox balance

    Biomaterials

    (2019)
  • K. Zhao et al.

    Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury

    J. Biol. Chem.

    (2004)
  • Y. Mo et al.

    SS-31 reduces inflammation and oxidative stress through the inhibition of Fis1 expression in lipopolysaccharide-stimulated microglia

    Biochem. Biophys. Res. Commun.

    (2019)
  • D. Liu et al.

    Enhanced efficiency of mitochondria-targeted peptide SS-31 for acute kidney injury by pH-responsive and AKI-kidney targeted nanopolyplexes

    Biomaterials

    (2019)
  • T.M. Allen et al.

    Liposomal drug delivery systems: from concept to clinical applications

    Adv. Drug Deliv. Rev.

    (2013)
  • A. Yadav et al.

    Resveratrol loaded solid lipid nanoparticles attenuate mitochondrial oxidative stress in vascular dementia by activating Nrf2/HO-1 pathway

    Neurochem. Int.

    (2018)
  • S. Sarkar et al.

    Protective roles of nanomelatonin in cerebral ischemia-reperfusion of aged brain: Matrixmetalloproteinases as regulators

    Exp. Gerontol.

    (2017)
  • Y. Bae et al.

    Dequalinium-based functional nanosomes show increased mitochondria targeting and anticancer effect

    Eur. J. Pharm. Biopharm.

    (2018)
  • G. Gamboa-Vujicic et al.

    Toxicity of the mitochondrial poison dequalinium chloride in a murine model system

    J. Pharm. Sci.

    (1993)
  • Y. Yamada et al.

    MITO-Porter: a liposome-based carrier system for delivery of macromolecules into mitochondria via membrane fusion

    Biochim. Biophys. Acta

    (2008)
  • Y. Yamada et al.

    A dual-Ligand liposomal system composed of a cell-penetrating peptide and a mitochondrial RNA aptamer synergistically facilitates cellular uptake and mitochondrial targeting

    J. Pharm. Sci.-US

    (2016)
  • Y. Yamada et al.

    Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver

    J. Control. Release

    (2015)
  • M. Hibino et al.

    The use of a microfluidic device to encapsulate a poorly water-soluble drug CoQ10 in lipid nanoparticles and an attempt to regulate intracellular trafficking to reach mitochondria

    J. Pharm. Sci.

    (2019)
  • S. Vyas et al.

    Mitochondria and Cancer

    Cell

    (2016)
  • P.E. Porporato et al.

    A mitochondrial switch promotes tumor metastasis

    Cell Rep.

    (2014)
  • M.P. Murphy

    Selective targeting of bioactive compounds to mitochondria

    Trends Biotechnol.

    (1997)
  • S. Biswas et al.

    Liposomes loaded with paclitaxel and modified with novel triphenylphosphonium-PEG-PE conjugate possess low toxicity, target mitochondria and demonstrate enhanced antitumor effects in vitro and in vivo

    J. Control. Release

    (2012)
  • M. Lindgren et al.

    Cell-penetrating peptides

    Trends Pharmacol. Sci.

    (2000)
  • K.L. Horton et al.

    Mitochondria-penetrating peptides

    Chem. Biol.

    (2008)
  • K.P. Mahon et al.

    Deconvolution of the cellular oxidative stress response with organelle-specific peptide conjugates

    Chem. Biol.

    (2007)
  • S.P. Wisnovsky et al.

    Targeting mitochondrial DNA with a platinum-based anticancer agent

    Chem. Biol.

    (2013)
  • S.B. Fonseca et al.

    Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells

    Chem. Biol.

    (2011)
  • T. Zhao et al.

    Mitochondria penetrating peptide-conjugated TAMRA for live-cell long-term tracking

    Bioconjug. Chem.

    (2019)
  • A. Klimpel et al.

    Bifunctional peptide hybrids targeting the matrix of mitochondria

    J. Control. Release

    (2018)
  • Y. Cheng et al.

    Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity

    J. Control. Release

    (2020)
  • J. Song et al.

    Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways

    J. Control. Release

    (2019)
  • D.C. Wallace

    A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine

    Annu. Rev. Genet.

    (2005)
  • V. Weissig

    From serendipity to mitochondria-targeted nanocarriers

    Pharm. Res.

    (2011)
  • J. Trnka et al.

    Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak

    PLoS One

    (2015)
  • M.J. Rossman et al.

    Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults

    Hypertension

    (2018)
  • K. Du et al.

    Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity

    Arch. Toxicol.

    (2017)
  • M. Velichkovska et al.

    Targeted mitochondrial COQ10 delivery attenuates antiretroviral-drug-induced senescence of neural progenitor cells

    Mol. Pharm.

    (2019)
  • A. Sharma et al.

    Targeting mitochondrial dysfunction and oxidative stress in activated microglia using dendrimer-based therapeutics

    Theranostics

    (2018)
  • H.H. Szeto

    Mitochondria-targeted peptide antioxidants: novel neuroprotective agents

    AAPS J.

    (2006)
  • P.W. Schiller et al.

    Type and location of fluorescent probes incorporated into the potent mu-opioid peptide [Dmt]DALDA affect potency, receptor selectivity and intrinsic efficacy

    J. Pept. Res.

    (2005)
  • H.H. Szeto

    Cell-permeable, mitochondrial-targeted, peptide antioxidants

    AAPS J.

    (2006)
  • H.H. Szeto

    First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics

    Br. J. Pharmacol.

    (2014)
  • H.H. Szeto et al.

    Serendipity and the discovery of novel compounds that restore mitochondrial plasticity

    Clin. Pharmacol. Ther.

    (2014)
  • I. Escribano-Lopez et al.

    The mitochondrial antioxidant SS-31 modulates oxidative stress, endoplasmic reticulum stress, and autophagy in type 2 diabetes

    J. Clin. Med.

    (2019)
  • Cited by (54)

    • Therapeutic potential of engineering the mitochondrial genome

      2023, Biochimica et Biophysica Acta - Molecular Basis of Disease
    View all citing articles on Scopus
    View full text