Friedreich\'s ataxia (FRDA) is a progressive neurodegenerative disease caused in almost all patients by expanded guanine-adenine-adenine (GAA) trinucleotide repeats within intron 1 of the FXN gene. This results in a relative deficiency of frataxin, a small nucleus-encoded mitochondrial protein crucial for iron-sulfur cluster biogenesis. Currently, there is only one medication, omaveloxolone, available for FRDA patients, and it is limited to patients 16 years of age and older. This necessitates the development of new medications. Frataxin restoration is one of the main strategies in potential treatment options as it addresses the root cause of the disease. Comprehending the control of frataxin at the transcriptional, post-transcriptional, and post-translational stages could offer potential therapeutic approaches for addressing the illness. This review aims to provide a general overview of the regulation of frataxin and its implications for a possible therapeutic treatment of FRDA.

Metabolic syndrome (MetS) is a complex pathological condition that involves disrupted carbohydrate, protein, and fat metabolism in the human body, and is a major risk factor for several chronic diseases, including diabetes, cardiovascular disease, and cerebrovascular disease. While the exact pathogenesis of metabolic syndrome is not yet fully understood, there is increasing evidence linking mitochondrial dysfunction, which is closely related to the mitochondrial genome and mitochondrial dynamics, to the development of this condition. Recent advancements in genetic sequencing technologies have allowed for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with metabolic syndrome. Additionally, the identification of specific mechanisms by which reduced mtDNA copy number and gene mutations, as well as abnormalities in mtDNA-encoded proteins and mitochondrial dynamics, contribute to metabolic syndrome may promote the development of novel therapeutic targets and interventions, such as the restoration of mitochondrial function through the targeting of specific mitochondrial defects. Additionally, advancements in genetic sequencing technologies may allow for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with MetS. Therefore, strategies to promote the restoration of mitochondrial function by addressing these defects may offer new options for treating MetS. This review provides an overview of the research progress and significance of mitochondrial genome and mitochondrial dynamics in MetS.

Mitochondria, the main provider of energy in eukaryotic cells, contains more than 1000 different proteins and is closely related to the development of cells. However, damaged proteins impair mitochondrial function, further contributing to several human diseases. Evidence shows mitochondrial proteases are critically important for protein maintenance. Most importantly, quality control enzymes exert a crucial role in the modulation of mitochondrial functions by degrading misfolded, aged, or superfluous proteins. Interestingly, cancer cells thrive under stress conditions that damage proteins, so targeting mitochondrial quality control proteases serves as a novel regulator for cancer cells. Not only that, mitochondrial quality control proteases have been shown to affect mitochondrial dynamics by regulating the morphology of optic atrophy 1 (OPA1), which is closely related to the occurrence and progression of cancer. In this review, we introduce mitochondrial quality control proteases as promising targets and related modulators in cancer therapy with a focus on caseinolytic protease P (ClpP), Lon protease (LonP1), high-temperature requirement protein A2 (HrtA2), and OMA-1. Further, we summarize our current knowledge of the advances in clinical trials for modulators of mitochondrial quality control proteases. Overall, the content proposed above serves to suggest directions for the development of novel antitumor drugs.

Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions.

Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt.

The brain is one of the most energetically demanding tissues in the human body, and mitochondrial pathology is strongly implicated in chronic neurodegenerative diseases. In contrast to acute brain injuries in which bioenergetics and cell death play dominant roles, studies modeling familial neurodegeneration implicate a more complex and nuanced relationship involving the entire mitochondrial life cycle. Recent literature on mitochondrial mechanisms in Parkinson\'s disease, Alzheimer\'s disease, frontotemporal dementia, Huntington\'s disease, and amyotrophic lateral sclerosis is reviewed with an emphasis on mitochondrial quality control, transport and synaptodendritic calcium homeostasis. Potential neuroprotective interventions include targeting the mitochondrial kinase PTEN-induced kinase 1 (PINK1), which plays a role in regulating not only multiple facets of mitochondrial biology, but also neuronal morphogenesis and dendritic arborization.

The filamentous ascomycete Podospora anserina is a well-established model system to study organismic aging. Its senescence syndrome has been investigated for more than fifty years and turned out to have a strong mitochondrial etiology. Several different mitochondrial pathways were demonstrated to affect aging and lifespan. Here, we present an update of the literature focusing on the cooperative interplay between different processes.

Targeting cancer metabolism has emerged as an attractive approach to improve therapeutic regimens in acute myeloid leukaemia (AML). Mitochondrial proteases are closely related to cancer metabolism, but their biological functions have not been well characterized in AML. According to different categories, we comprehensively review the role of mitochondrial proteases in AML. This review highlights some \'powerful\' mitochondrial protease targets, including their biological function, chemical modulators, and applicative prospect in AML.

Increasing evidence indicates that a mitochondria-specific stress response referred to as the \'mitochondrial unfolded protein response\' (UPRmt) is activated to maintain mitochondrial integrity and support tumor growth. In this forum article, we discuss the recent advances and current challenges in therapeutically targeting UPRmt in cancer.

Mitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain, and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis, presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged, or superfluous proteins. Depending on their different functions and substrates, defects in mitochondrial proteases can affect the majority of the mitochondrial proteome or only a single protein. Consequently, mutations in mitochondrial proteases have been linked to several human diseases. This review gives an overview of the components and functions of the mitochondrial proteolytic machinery and highlights the pathological consequences of dysfunctional mitochondrial protein processing and turnover.