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Mitochondria: From Physiology to Pathology

Article  in  Life · September 2021

DOI: 10.3390/life11090991

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 life

Editorial
Mitochondria: From Physiology to Pathology
Francesco Bruni

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4,
70125 Bari, Italy; francesco.bruni@uniba.it

Over the past decade, the role of mitochondria has extended beyond those tasks for
which these organelles are historically known. Recent proteomics investigations have
highlighted the extraordinary complexity of mitochondrial protein organization, which
is a reflection of the numerous and disparate mitochondrial functions [1]. These include
the synthesis of most of the ATP present in the cell, apoptosis, ion homeostasis, cellular
stress response, antioxidant control, redox regulation, mitophagy, involvement in various
biosynthetic pathways and many more processes. Furthermore, mitochondria are dynamic
organelles, and their morphology can vary significantly within a cell. This is mainly due
to the mitochondrial fusion and fission processes, referred as mitochondrial dynamics,
which are crucial for the organelles’ interactions with other cell compartments and for the
cross-talk with the cell cycle and metabolism as well as differentiation and senescence [2].
An intriguing feature of mitochondria is that they possess their own DNA (mtDNA),
which is functionally coordinated with the nuclear genome. Indeed, numerous nucleus-
encoded proteins are required for complex molecular processes such as replication, tran-
scription, RNA processing and degradation, translation, and assembly of respiratory chain
complexes that take place inside the mitochondria [3,4]. On the other hand, mitochondrial
gene expression plays an important role in the communication between mitochondria and




the nucleus, contributing to the regulation of cell physiology. Recent studies have pointed

 to novel RNA-driven mechanisms according to which mitochondrial-derived transcripts,
Citation: Bruni, F. Mitochondria: in addition to their role in maintaining mitochondrial function, act as signalling molecules
From Physiology to Pathology. Life modulating the innate immune response [5].
2021, 11, 991. https://doi.org/ Dysfunctions affecting the mitochondria can lead to various pathological conditions,
10.3390/life11090991 including aging and neurodegenerative disorders, and are associated with a whole range
of complex genetic disorders, known as mitochondrial diseases [6]. In recent years, great
Received: 17 September 2021 advances have been made in the field of mitochondrial diagnostics thanks to the rapid devel-
Accepted: 19 September 2021 opment of next-generation sequencing (NGS) technologies, particularly the whole-genome
Published: 21 September 2021 approach [7]. However, most of the aspects and mechanisms underlying mitochondrial
diseases remain unclear and, to date, effective therapies are still lacking. Therefore, a
Publisher’s Note: MDPI stays neutral thorough understanding of the molecular processes occurring in mitochondria is essential
with regard to jurisdictional claims in from a pathological perspective.
published maps and institutional affil- The Special Issue “Mitochondria: from Physiology to Pathology” published in Life
iations. (ISSN 2075-1729) collects a series of research and review articles and aims to provide an
updated view of the main topics covering the physiological and the pathological aspects of
mitochondrial biology.
Several contributions focus on the mitochondrial genome and its link to the phys-
Copyright: © 2021 by the author. iopathological aspects of the various mitochondrial processes. Chapman et al. [8] present
Licensee MDPI, Basel, Switzerland. a comprehensive review on mtDNA metabolism, highlighting the interplay occurring
This article is an open access article between the organization of the mitochondrial genome, mitochondrial dynamics and
distributed under the terms and cristae structure. After a brief excursus on the organization of mtDNA and on its main
conditions of the Creative Commons processes, such as replication and transcription, the authors deal in depth with the pro-
Attribution (CC BY) license (https:// cesses of fission and fusion relative to the structure of mtDNA, discussing the known
creativecommons.org/licenses/by/
genetic defects that affect mitochondrial dynamics. To complete the picture, they describe
4.0/).

Life 2021, 11, 991. https://doi.org/10.3390/life11090991 https://www.mdpi.com/journal/life

Life 2021, 11, 991 2 of 4

the close relationship between the nucleoid, OPA1 and the other “cristae-shaping pro-
teins” constituting the MICOS complex, whose interactions modulate the formation and
dynamics of mitochondrial cristae. These are critical process that, if not well regulated,
can prompt mitochondrial dysfunction with the onset of neuromuscular diseases. Another
important process whose dysregulation can lead to severe pathologies is the elimination of
mitochondrial genome. Orishchenko and colleagues [9] review the mechanisms underlying
the regulation of heteroplasmy level and mtDNA segregation, illustrating in detail the
natural process of mitochondrial genome elimination in both the somatic cells and the
germline. The development of methodologies for artificial manipulation of the mtDNA
heteroplasmy level that aim either to prevent or potentially cure human diseases associated
with mitochondrial dysfunction, is also examined.
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS)
is a metabolic disorder caused by point mutations in the mitochondrial tRNALeu(UUR) gene,
with a prevalence of A>G substitution in position 3243. Several papers have reported that
overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) or its C-terminal
domain (Cterm) has proven effective in rescuing the pathological phenotype in cellular
models. In their research article, Capriglia et al. [10] investigated the molecular basis
underlying the ability of the Cterm domain in rescuing the MELAS phenotype. The cellular
model employed, consisting of a trans-mitochondrial cybrid line with a >95% mutation load,
confirmed the therapeutic potential of the Cterm peptide but also showed that its rescuing
ability was independent of the mitochondrial bioenergetics, unlike what has previously
been observed in other cybrid lines. The authors proposed that the beneficial effect of this
peptide could also be mediated by retrograde mitochondrial signals or, alternatively, by its
potential ability to bind regulatory RNA in the cytosol. This research indicates that the full
understanding of Cterm-rescuing mechanisms imposes the development of tissue-specific
cellular models that accurately reproduce the pathological MELAS phenotype.
Another study, based on a cohort of 468 subjects from the Siberian region, was con-
ducted by Kirichenko et al. [11] with the purpose of determining the impact of mitochon-
drial heteroplasmy measurements in the prognosis of atherosclerosis development. They
investigated the association of nine different mtDNA mutations with carotid intima-media
thickness (cIMT), a measurement of the artery wall thickness obtained by ultrasound imag-
ing. Several mtDNA variants correlated with the mean cIMT, thus constituting potential
prognostic markers. Interestingly, the mutations m.13513G>A and m.14846G>A showed
a significant inverse correlation being associated with a low value of cIMT, representing
good candidates for the development of anti-atherosclerotic gene therapies.
The dysregulation of mitochondrial functions certainly depends on faulty mitochon-
drial gene expression at different levels, but also on other factors. One of these, which takes
on particular importance in mitochondrial physiology, is the post-translational modifica-
tion of mitochondrial proteins. Phosphorylation is commonly employed in mitochondria
either to modify protein functions or to activate fundamental signalling pathways, inside
and outside the mitochondria. Kotrasová et al. [12] center their review on mitochondrial
kinases and their role in keeping organelles fully efficient. This function is exerted on
various and distinct substrates: mitochondrial import machinery, subunits of respiratory
chain complexes and proteins involved in the main steps of mtDNA maintenance and
expression. In addition, the activity of mitochondrial kinases is also important for organelle
quality control and apoptosis. One of the central key players in mitochondrial quality
control pathways is PINK1 (PTEN-induced kinase 1). Barroso Gonçalves and Morais [13]
emphasize how valuable the supply of PINK1 is for the mitochondrial clearance through
mitophagy and for the maintenance of mitochondrial homeostasis, thereby keeping cells
healthy and functional. The precise mechanisms that mediate PINK1 function in the dif-
ferent mitochondrial pathways remain to be elucidated. Nevertheless, the genetic link
between PINK1 and Parkinson’s Disease (PD) has long been proven, particularly for the
familial form of this pathology. Further research needs to be carried out to define whether
the mitochondrial homeostasis imbalance, due to the aberrant function of PINK1, is the key
Life 2021, 11, 991 3 of 4

element that contributes to the pathological phenotype in both the familiar and sporadic
forms of PD.
An important aspect of mitochondrial physiology is its hormone-mediated regulation.
Medar et al. [14] analysed mitochondrial response to luteinizing hormone (LH) stimulation
in Leydig cells, the major producers of steroid hormones that regulate sexual differentiation
and development. In these cells, endocrine function requires the cAMP signalling pathway,
whose involvement in modulating respiratory chain complexes activity, ATP production,
biogenesis, import, dynamics, and mitochondrial-dependent apoptosis has been widely
investigated. The reported results, obtained by different experimental approaches in rat
Leydig cells ex vivo and in vivo with a different LH environment and steroidogenic capacity,
supported the involvement of LH-cAMP pathway in the regulation of mitochondrial
biogenesis and dynamics coupled with mitochondria-mediated steroidogenesis. Additional
studies carried out in Leydig and other steroidogenic cells, e.g., derived from adrenal glands
and placenta, will shed light on the pathogenic mechanisms triggered by the presence of
unhealthy mitochondria in these tissues.
The last research article of this Special Issue focuses on the Saccharomyces cerevisiae
FAD1 gene, encoding the FAD synthase that adenylates the flavin mononucleotide (FMN)
to flavin adenine dinucleotide (FAD), an essential coenzyme for various flavoenzymes.
Barile and colleagues previously proved that FAD-forming activities, paralleled by FAD
precursors uptake in mitochondria and mitochondrial FAD export to cytosol, could be
specifically revealed in mitochondria. However, a protein responsible for the synthesis
of FAD had never been identified in yeast mitochondria. In this paper [15], the presence
of two Fad1p echoforms, dually localised to the cytosol and mitochondria, was reported.
Intriguingly, the authors demonstrated the existence of two pools of FAD1 mRNAs with
3’ untranslated regions (UTRs) of different length and containing a mitochondrial targeting
signal. Therefore, the 30 UTRs would be responsible for the fate of Fad1p echoforms, with
the long FAD1 mRNA generating the mitochondrial Fad1p. In this context, the authors
discussed the role of specific RNA binding proteins (e.g., Puf3p) that modulate the import
of the mitochondrial Fad1p echoform. Overall, the paper adds a useful piece of knowledge
to the post-transcriptional control of genes encoding mitochondrial proteins, proposing the
existence of novel regulatory mechanisms in yeast as well as in higher eukaryotes.

Author Contributions: F.B. wrote the manuscript. All authors have read and agreed to the published
version of the manuscript.
Funding: Fondi di Ateneo “Contributo Ordinario di Supporto alla Ricerca” 2015/16 and 2017/18
(University of Bari Aldo Moro) to F.B.
Acknowledgments: The guest editor wishes to thank Pasqua Gramegna for the critical reading
of the manuscript and Veronica Wang for her precious help with the editorial process. All the
contributors and those involved in the peer-review activity of the Special Issue of Life ‘Mitochondria:
from Physiology to Pathology’ are gratefully acknowledged.
Conflicts of Interest: The author declares no conflict of interest.

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