Cell and Tissue Research (2019) 377:161–165 https://doi.org/10.1007/s00441-019-03049-z MINI REVIEW Mitochondrial peptides—appropriate options for therapeutic exploitation Lucia-Doina Popov1 Received: 12 April 2019 /Accepted: 10 May 2019 /Published online: 27 May 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Besides their well-known function in cellular bioenergetics, the role of mitochondria in signaling regulation of cells homeostasis and survival has been uncovered during the past few decades. Possessing an independent genome and a unique genetic code, mitochondria biosynthesize protective stress response factors, the Bmitochondrial-derived peptides,^ import and deposit peptides within their matrix and are the target of peptides bound to bioactive agents, aiming at alleviation of pathology-related malfunction of the electron transport chain. As the rapidly evolving field of mitochondrial peptides is appropriate for therapeutic exploitation, a brief overview of the major recent findings is timely needed. Here, the focus is on the following issues: (i) the biological effects of mitochondrial-derived peptides (humanin, humanin-like peptides and MOTS-c) and their use in therapy, (ii) the abnormal accumulation of β-amyloid peptide within the mitochondrial matrix and (iii) the effectiveness of Bmitochondrial cell-penetrating/ targeting peptides^ as vehicles for delivery of bioactive agents into dysfunctional mitochondria. Keywords mtDNA . β-Amyloid . Humanin . Cell-penetrating peptides . Mitochondrial targeted peptides Introduction functional Bmitochondrial-derived peptides^ (MDPs). This class of peptides comprises humanin, humanin-like peptides Mitochondria are well-known intracellular organelles with a and MOTS-c and expands the expression of mitochondrial vital role in ATP biosynthesis and thus, in cellular bioenerget- proteome (Kim et al. 2018). ics. Owing to their prokaryotic origin, mitochondria execute the Bquorum sensing^ coordination of intracellular processes by sending Bretrograde^ signals such as Ca2+, ROS and cyto- Naturally occurring mitochondrial-derived chrome C. to the other intracellular organelles and to the cy- peptides tosol (Lee et al. 2013, 2015; Popov 2017). The mitochondrial genome inherits bacterial-like traits: the The first MDP discovered back in 2001 was Humanin (HN); DNA molecules (mtDNA) are circular, double stranded, small the term originates from Nishimoto’s group based on the po- (16,569 nucleotides in humans) and compact. mtDNA con- tential of this peptide for restoring the Bhumanity^ of tains 37 genes, including 22 tRNAs, 2 rRNAs (12S and 16S Alzheimer’s disease (AD) patients (Hashimoto et al. 2001). rRNA) and 13 mRNAs encoding the proteins of the electron HN is encoded by the 75 bp ORF sequence within the 16S transport chain (Cobb et al. 2016; Lee et al. 2013, 2016). The rRNA gene of mtDNA. In response to cellular stress, HN is mtDNA has no introns but a few non-coding nucleotides be- secreted as a peptide made of 24 or 21 amino acids, depending tween adjacent genes and Bsmall open reading frames^ on the cytoplasmic or mitochondrial translation site, respec- (sORF, smaller than or equal to 300 nucleotides) that encode tively. At the neuronal cell surface, HN binds to a receptor composed of ciliary neurotrophic factor receptor α, the cyto- kine receptor WSX-1 and the transmembrane gp130 * Lucia-Doina Popov (heterotrimeric HN receptor); moreover, HN proved to be an [email protected]; [email protected] endogenous agonist peptide of the formyl peptide receptor 2 1 Institute of Cellular Biology and Pathology BNicolae Simionescu^ of (Hashimoto et al. 2013). the Romanian Academy, 8, B.P. Hasdeu Street, The intracellular roles of HN are as follows: (i) involve- 050568 Bucharest, Romania ment in the retrograde signaling pathway from the 162 Cell Tissue Res (2019) 377:161–165 mitochondria to the nucleus (Cobb et al. 2016); (ii) participa- misfolding, a key step in type 2 diabetes mellitus (Okada tion as a stress-responsive, cell survival factor (Nashine et al. et al. 2017). Specifically, SHLP2 has the following biological 2017); HN is cytoprotective against oxidative stressors, by effects: (i) acts as an insulin sensitizer, which operates both activation of the chaperone-mediated autophagy pathway peripherally and centrally (Cobb et al. 2016), (ii) restores the (Gong et al. 2018), (iii) protection from cells death by inhibi- normal levels of oxidative phosphorylation chain protein sub- tion of ROS generation, upregulation of mitochondrial GSH units, (iii) increases the number of mtDNA copies, (iv) re- and activation of caspase 3 and 4 (Minasyan et al. 2017), (iv) duces amyloid-β-induced cellular and mitochondrial toxicity defense against endoplasmic reticulum (ER) stress, by resto- and (v) has anti-apoptotic outcomes (Nashine et al. 2018). ration of the depleted mitochondrial glutathione (GSH) level Moreover, in AMD cells, in vitro, SHLP2 exerts protective (Sreekumar et al. 2017). effects (Nashine et al. 2018). HN has beneficial effects in pathologies that involve both The mitochondrial open-reading-frame of the 12S rRNA-c oxidative and ER stress, such as stroke, myocardial infarction, (MOTS-c, mitochondrial ORF of the twelve S c) (Lee et al. diabetes, cancer (Gong et al. 2018) and atherosclerosis (Lee 2015) is a recently identified MDP composed of 16 amino et al. 2013). HN treatment is neuroprotective in AD, by acids. Following stress induction, MOTS-c translocates into defending cells from β-amyloid (Aβ) toxicity (Cobb et al. the nucleus, binds to DNA and regulates transcription of stress 2016) and in age-related macular degeneration (AMD), a lead- response genes in the mitochondrial - nucleus crosstalk (Kim ing cause of blindness among the elderly population et al. 2018). Although MOTS-c signaling is only partially (Sreekumar et al. 2017). uncovered at present, the current data support numerous im- The analog of HN, humanin G (HNG) (in which the serine plications of this peptide in mediation of metabolic homeosta- 14 was replaced by glycine), has cardioprotective effects in sis, mitohormesis, cell survival, stimulation of glucose metab- myocardial ischemia reperfusion injury in vivo, by attenuation olism and insulin sensitivity (especially in the skeletal mus- of oxidative stress and activation of antioxidant defense mech- cle), as well as in the regulation of diet-induced obesity, dia- anisms (Klein et al. 2013). betes and longevity (Lee et al. 2015, 2016). HNG may be a potential therapeutic solution in dry AMD, an eye disease with no available treatment at present (Klein et al. 2013; Nashine et al. 2017). Mitochondrial matrix, a site for Aβ-peptides Recently, six additional peptides encoded within the mito- accumulation chondrial 16S rRNA region of mtDNA have been discovered and designed as Small HN-like peptides (SHLP1-6) (Fig. 1) It has been established that mitochondria can import cytosolic (Cobb et al. 2016; Nashine et al. 2018). SHLP2 and SHLP3 peptides. For Aβ-peptides present in the brain of AD patients, share similar biological effects with HN: are cytoprotective the issue starts with the γ-secretase complex located at and enhance mitochondrial metabolism (Cobb et al. 2016). mitochondria-associated endoplasmic reticulum membranes, Both HNG and SHLP2 inhibit islet amyloid polypeptide the intracellular site of Aβ production (Pinho et al. 2014). Fig. 1 The mitochondrion- peptides relationship: the mitochondrial ribosomal RNAs biosynthesis of Bmitochondria- derived peptides^ (MDPs) and the mitochondrial matrix dual function: a deposit for β-Amyloid and a target for the bioactive cargoes transported by the chem- ical synthesized vectors such as the Bcell-penetrating peptides^ (CPPs), Bmitochondrial-penetrat- ing peptides^ (mtCPPs) and Bmitochondria-targeted peptides^ (MTPs). HN, humanin; HNG, humanin G; humanin-like pep- tides (SHLP1-6) and MOTS-c Cell Tissue Res (2019) 377:161–165 163 Next, the mitochondrial translocase TOMM22 (in humans) penetrating peptides^ (mtCPPs). Recently, dual constructs recognizes the cytosolic Aβ and transfers it to TOMM40, with augmented scavenging ability have been launched: (i) another translocase subunit. Then, the peptide chain is direct- the mtCPP1-UPF25 (where mtCPP1 targets mitochondria, ed to the TOMM channel and enters mitochondria via the N- whereas UPF25—an antioxidative GSH analog—is active terminal Bpre^sequence, a structural prerequisite for import within the cytosol (Cerrato and Langel 2017) and (ii) the li- (Hu et al. 2018). Another key reaction takes place within the posomal system made of a CPP and a mitochondrial RNA mitochondrial matrix, where the Bpre^sequence (the aptamer; it has a higher mitochondrial targeting activity via hydrophobic fragment Aβ35-40) is cleaved by the an ATP-dependent pathway (Yamada et al. 2016). Bpre^sequence protease (PreP) in cooperation with neurolysin The Bcell-penetrating mitochondrial transit peptides^ peptidase (Taskin et al. 2017; Teixeira et al. 2018). This is a (CpMTP) is another term found in the literature for the turning point, as impairment or reduced efficiency of the mitochondrial-targeted CPPs (Jain and Chugh 2016). This cleaving reaction, causes PreP inhibition followed by abnor- term may be confusing due to the existence of a distinct class mal accumulation of toxic, immature Aβ within the matrix of Bmitochondria-targeted peptides^ (MTPs) that penetrate all and by mitochondrial dysfunction (respiratory chain malfunc- cells (even the blood-brain barrier) and transport