Here, we report on validating a mitochondrial gene therapy by delivering nucleic acids to mitochondria of diseased cells by a MITO-Porter, a liposome-based carrier for mitochondrial delivery. We used cells derived from a patient with a mitochondrial disease with a G625A heteroplasmic mutation in the tRNA^Phe of the mitochondrial DNA (mtDNA). It has been reported that some mitochondrial gene diseases are caused by heteroplasmic mutations, in which both mutated and wild-type (WT) genes are present, and the accumulation of pathological mutations leads to serious, intractable, multi-organ diseases. Therefore, the decrease of the mutated gene rate is considered to be a useful gene therapy strategy. To accomplish this, wild-type mitochondrial pre-tRNA^Phe (pre-WT-tRNA^Phe), prepared by in vitro transcription, was encapsulated in the MITO-Porter. The pre-WT-tRNA^Phe encapsulated in the MITO-Porter was transfected into diseased mitochondrial cells, and the resulting mutant levels were examined by an amplification refractory mutation system (ARMS)-quantitative PCR. The mutation rate of tRNA^Phe was decreased, and this therapeutic effect was sustained even on the 8th day after transfection. Furthermore, mitochondrial respiratory activity of the disease cells was increased after the transfection of therapeutic pre-WT-tRNA^Phe. These results support the conclusion that the mitochondrial delivery of therapeutic nucleic acids represents a viable strategy for mitochondrial gene therapy.

There have been many reports on the relationship between mitochondrial oxidative stress and various types of diseases. This review covers mitochondrial targeting photodynamic therapy and photothermal therapy as a therapeutic strategy for inducing mitochondrial oxidative stress. We also discuss other mitochondrial targeting phototherapeutic methods. In addition, we discuss anti-oxidant therapy by a mitochondrial drug delivery system (DDS) as a therapeutic strategy for suppressing oxidative stress. We also describe cell therapy for reducing oxidative stress in mitochondria. Finally, we discuss the possibilities and problems associated with clinical applications of mitochondrial DDS to regulate mitochondrial oxidative stress.

The convex envelopes of the direct discrete measures, for the sparsity of vectors or for the low-rankness of matrices, have been utilized extensively as practical penalties in order to compute a globally optimal solution of the corresponding regularized least-squares models. Motivated mainly by the ideas in Zhang (2010 Ann. Stat . 38 894–942; Selesnick 2017 IEEE Trans. Signal Process . 65 4481–94; Yin et al 2019 IEEE Trans. Signal Process . 67 2595–607) to exploit nonconvex penalties in the regularized least-squares models without losing their overall convexities, this paper presents the linearly involved generalized Moreau enhanced (LiGME) model as a unified extension of such utilizations of nonconvex penalties. The proposed model can admit multiple nonconvex penalties without losing its overall convexity and thus is applicable to much broader scenarios in the sparsity-rank-aware signal processing. Under the general overall-convexity condition of the LiGME model, we also present a novel proximal splitting type algorithm of guaranteed convergence to a globally optimal solution. Numerical experiments in typical examples of the sparsity-rank-aware signal processing demonstrate the effectiveness of the LiGME models and the proposed proximal splitting algorithm.