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Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders

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ABSTRACT

Protein therapy is considered an alternative approach to gene therapy for treatment of genetic-metabolic disorders. Human protein therapeutics (PTs), developed via recombinant DNA technology and used for the treatment of these illnesses, act upon membrane-bound receptors to achieve their pharmacological response. On the contrary, proteins that normally act inside the cells cannot be developed as PTs in the conventional way, since they are not able to “cross” the plasma membrane. Furthermore, in mitochondrial disorders, attributed either to depleted or malfunctioned mitochondrial proteins, PTs should also have to reach the subcellular mitochondria to exert their therapeutic potential. Nowadays, there is no effective therapy for mitochondrial disorders. The development of PTs, however, via the Protein Transduction Domain (PTD) technology offered new opportunities for the deliberate delivery of human recombinant proteins inside eukaryotic subcellular organelles. To this end, mitochondrial disorders could be clinically encountered with the delivery of human mitochondrial proteins (engineered via recombinant DNA and PTD technologies) at specific intramitochondrial sites to exert their function. Overall, PTD-mediated Protein Replacement Therapy emerges as a suitable model system for the therapeutic approach for mitochondrial disorders.

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Abbreviations

aa:

amino acids

CDS:

coding sequence

CNS:

central nervous system

COX:

Cytochrome c Oxidase

E. coli :

Escherichia coli

ERT:

Enzyme Replacement Therapy

FDA:

Food and Drug Administration

GFP:

Green Fluorescent Protein

GMOs:

genetically modified organisms

IBs:

inclusion bodies

IMS:

intermembrane space

IPTG:

isopropyl-beta-D-thiogalactopyranoside

L:

N-terminal Leader Peptide

LAD:

Lipoamide Dehydrogenase

mab:

monoclonal antibody

MPP:

Mitochondrial Processing Peptidase

mtDNA:

mitochondrial DNA

MTS:

Mitochondrial Targeting Signal Peptide

ΝABs:

Neutralizing Antibodies

nDNA:

muclear DNA

OXPHOS:

Oxidative Phosphorylation System

PDHC:

Pyruvate Dehydrogenase Complex

PEG:

poly(ethylene glycol)

PRT:

Protein Replacement Therapy

PTD:

Protein Transduction Domain

PTs:

Protein Therapeutics

ROS:

Reactive Oxygen Species

TAT:

a Protein Transduction Domain

TCA:

Tricarboxylic acid cycle

TFAM:

Mitochondrial Transcription Factor A

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ACKNOWLEDGMENTS & DISCLOSURES

We would like to thank Mrs. Elena Kounadi (University Studio Press, Thessaloniki, Greece) for her artistic assistance and Mr. Ioannis D. Bonovolias, PhD student, for reading the manuscript.

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  1. Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki (A.U.TH.), Thessaloniki, GR54124, Macedonia, Greece

    Lefkothea C. Papadopoulou & Asterios S. Tsiftsoglou

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  1. Lefkothea C. Papadopoulou
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  2. Asterios S. Tsiftsoglou
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Correspondence to Lefkothea C. Papadopoulou.

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Papadopoulou, L.C., Tsiftsoglou, A.S. Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders. Pharm Res 28, 2639–2656 (2011). https://doi.org/10.1007/s11095-011-0546-y

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