Mitochondrial Stress Signaling and Disease

Mitochondrial functional disturbance can activate a series of stress signals to restore energy metabolism, protein homeostasis, and redox balance. Decreased membrane potential, impaired respiratory chain function, defective protein import, or abnormal mitochondrial proteostasis can induce multiple stress responses, including the ISR, UPRmt, mitophagy, and mitochondrial factor secretion. Short-term stress helps cells adapt, whereas long-term or abnormal activation may contribute to aging, tumors, neurodegenerative diseases, metabolic disorders, and chronic inflammation.

Keywords: mitochondrial stress; integrated stress response; DELE1; OMA1; HRI; ATF4; UPRmt; mitochondrial protein import; GDF15; FGF21; mitophagy; mitohormesis; disease mechanisms

1 Research Entry Points for Mitochondrial Stress

1.1 Main Sources of Mitochondrial Stress

Mitochondrial stress is not a single injury event, but an integrated response formed after abnormalities in mitochondrial membrane potential, oxidative phosphorylation, protein import, protein folding, mtDNA stability, and redox status. Different sources of stress can activate different signaling branches, but they often converge on proteostasis, metabolic remodeling, inflammatory regulation, and altered cell fate.

Stress Source	Direct Effect	Main Response Pathway
Respiratory chain impairment	ATP decline, NADH/NAD⁺ imbalance, ROS elevation	ISR, AMPK, redox response
Decreased membrane potential	Protein import defects, ion homeostasis disturbance	PINK1/Parkin, OMA1-DELE1-HRI
Mitochondrial protein misfolding	Impaired matrix proteostasis	UPRmt, mitochondrial protease system
Blocked mitochondrial protein import	Accumulation of precursor proteins in the cytosol	mPOS, mitoCPR, mitoRQC, etc.
mtDNA damage or release	Inflammation and immune recognition	cGAS-STING, TLR9, inflammasome
Increased mitochondrial ROS	Altered redox signaling	NRF2, ISR, mitohormesis
Abnormal mitochondrial dynamics	Imbalance among fusion, fission, and clearance	DRP1, MFN1/2, OPA1, mitophagy

1.2 Adaptive and Pathological Responses

Mitochondrial stress has a dual nature. Mild and transient mitochondrial pressure can enhance antioxidant capacity, protein quality control, and metabolic flexibility, representing protective mitohormesis. However, when stress is too strong or persists for too long, the same signals may shift toward pathological effects, promoting inflammation, cell death, tissue functional decline, or tumor adaptation.

Stress Intensity/Duration	Main Result	Biological Significance
Mild and transient	Metabolic adaptation and enhanced antioxidant capacity	Protective mitohormesis
Moderate and recoverable	Enhanced ISR, UPRmt, and mitophagy	Homeostatic repair
Strong and persistent	Proteostasis collapse, inflammation, and cell death	Disease progression
Chronic low-level	Adaptive cellular reprogramming	Aging, tumor tolerance, metabolic abnormalities

2 OMA1-DELE1-HRI Axis and the Integrated Stress Response

Figure 1. Mitochondrial Integrated Stress Response Mediated by the OMA1-DELE1-HRI-eIF2α-ATF4 Axis

2.1 OMA1 Senses Mitochondrial Functional Disturbance

OMA1 is a stress-sensitive protease located in the mitochondrial inner membrane. When mitochondrial membrane potential decreases, respiratory chain function is impaired, protein import becomes abnormal, or membrane protein homeostasis is disrupted, OMA1 can be activated and cleave mitochondrial-associated substrates. One of its important functions is to mediate DELE1 cleavage, thereby transmitting internal mitochondrial damage signals to the cytosolic ISR pathway.

OMA1 can be understood as a stress-sensing node in the mitochondrial inner membrane. When mitochondria cannot maintain normal membrane potential and protein homeostasis, OMA1 converts local mitochondrial pressure into a transcriptional response that can be sensed by the nucleus.

2.2 DELE1 Connects Mitochondria with Cytosolic Stress Kinases

DELE1 is a key protein in mitochondrial stress transmission. Under normal conditions, DELE1 is localized in mitochondria. When mitochondrial stress occurs, OMA1 can cleave DELE1 to produce a shorter cytosolic form, DELE1-S. After entering the cytosol, DELE1-S can bind and activate HRI.

In addition to OMA1-mediated cleavage, impaired mitochondrial protein import, low iron status, or translocation defects may also cause abnormal accumulation of full-length DELE1 on the outer side of mitochondria or in the cytosol, thereby participating in HRI activation. In other words, DELE1 not only responds to membrane potential-related damage, but also participates in broader stress recognition related to protein import and mitochondrial dysfunction.

2.3 HRI-eIF2α-ATF4 Mediates the ISR Transcriptional Program

After HRI is activated by DELE1, it can phosphorylate eIF2α. eIF2α phosphorylation suppresses global protein translation, but promotes translation of specific transcription factors such as ATF4. ATF4 then induces gene expression related to amino acid metabolism, antioxidant responses, proteostasis regulation, mitochondrial metabolic remodeling, and cell fate.

Node	Function	Result
Mitochondrial damage	Membrane potential decline, import blockage, proteostasis abnormality	Activates OMA1 or promotes abnormal DELE1 localization
OMA1	Cleaves DELE1	Generates cytosolic DELE1-S
DELE1	Activates HRI	Transmits mitochondrial stress to the ISR
HRI	Phosphorylates eIF2α	Suppresses global translation and alters stress protein synthesis
ATF4	Initiates stress transcriptional program	Regulates metabolism, antioxidant responses, proteostasis, and cell fate

2.4 Protective and Pathological Effects of the ISR

Short-term ISR activation helps reduce newly synthesized protein burden, adjust metabolism, enhance antioxidant capacity, and improve cell survival. If the ISR remains activated for a long period, it may cause excessive translation inhibition, reduced cellular function, increased inflammatory factor expression, or activation of apoptosis/death-related pathways.

In disease, the ISR may be either a protective mechanism or a pathological amplifier. Its role cannot be determined only by whether ATF4 is elevated. Stress duration, cell type, downstream target genes, and tissue functional changes must also be considered.

3 Impaired Mitochondrial Protein Import and Cytosolic Proteostasis Responses

3.1 Core Problem of Impaired Mitochondrial Protein Import

Most mitochondrial proteins are encoded by nuclear genes, synthesized in the cytosol, and imported into mitochondria through mitochondrial targeting sequences. If mitochondrial membrane potential declines, translocase complexes are damaged, or import channels are congested, precursor proteins carrying mitochondrial targeting sequences remain in the cytosol, creating proteostasis stress.

This stress affects not only mitochondria, but also the cytosolic protein quality control system. If mislocalized or stalled mitochondrial precursor proteins are not cleared in time, they may aggregate, interfere with proteasome capacity, and affect ER and cytosolic homeostasis.

3.2 Mitochondrial Import Stress Pathways in Yeast

In yeast models, impaired mitochondrial protein import can trigger multiple cooperative responses, including mPOS, mitoStore, mitoTAD, mitoCPR, and mitoRQC. These pathways share a common goal: to recognize, sequester, or clear proteins that fail to correctly enter mitochondria.

Pathway	Main Target	Functional Outcome
mPOS	Mitochondrial precursor proteins accumulated in the cytosol	Induces cytosolic proteostasis responses
mitoStore	Precursor proteins that are difficult to import in time	Temporarily stores them and limits toxicity
mitoTAD	Proteins stalled during mitochondrial membrane translocation	Promotes clearance of stalled proteins
mitoCPR	Proteins stalled in mitochondrial import channels	Promotes ubiquitination and proteasomal degradation
mitoRQC	Proteins related to abnormal translation or import	Maintains mitochondrial protein quality control
TA protein retargeting	Mislocalized tail-anchored proteins	Redirects them to the ER and promotes degradation

3.3 HSF1, the Proteasome, and the Ubiquitination System Participate in Coordinated Regulation

Mitochondrial protein import stress is not simply an internal mitochondrial problem. Cytosolic heat shock responses, the proteasome system, and ubiquitination pathways all participate in clearing mislocalized proteins. In yeast, HSF1, RPN4, and related transcriptional regulators can participate in this response and enhance protein folding, ubiquitination, and proteasomal degradation capacity. In mammalian cells, interpretation should instead consider HSF1, proteasome stress responses, and corresponding proteostasis regulators.

This mechanism suggests that mitochondrial stress can reshape the entire cellular proteostasis network. For neurons, muscle cells, tumor cells, and other cells with high metabolic demand or high protein synthesis pressure, impaired mitochondrial protein import may be especially important.

4 UPRmt and Mitochondrial Protein Quality Control

4.1 Basic Function of UPRmt

The mitochondrial unfolded protein response (UPRmt) is a transcriptional adaptation program initiated after mitochondrial proteostasis is impaired. Its core function is to increase the expression of mitochondrial chaperones, proteases, antioxidant factors, and metabolic remodeling genes to restore the mitochondrial protein folding environment.

Functional Module	Representative Molecules	Function
Protein folding	HSP60, mtHSP70	Promotes correct folding of mitochondrial proteins
Protein degradation	LONP1, CLPP	Clears misfolded or damaged proteins
Antioxidant response	SOD2, PRDX3	Reduces ROS-induced injury
Metabolic remodeling	Amino acid metabolism and mitochondrial metabolism-related genes	Adjusts energy and anabolic metabolism
Nuclear-mitochondrial communication	ATF5, CHOP, ATF4-related programs	Transmits mitochondrial stress to the nucleus

4.2 UPRmt and the ISR Intersect

UPRmt and the ISR are not completely independent pathways. Mitochondrial stress can simultaneously induce ATF4-related ISR programs and UPRmt-related transcriptional regulation involving ATF5, CHOP, and other factors. The two responses intersect in amino acid metabolism, redox regulation, mitochondrial proteostasis, and cell fate determination.

In experimental design, “UPRmt activation” should not be judged by a single marker. For example, detecting increased HSP60 alone is insufficient to demonstrate complete UPRmt activation. LONP1, CLPP, ATF5, CHOP, ATF4, and mitochondrial functional readouts should also be assessed together.

5 Mitochondrial Factors and Systemic Stress Signals

5.1 GDF15 and FGF21

Mitochondrial stress is not limited to individual cells; it can also affect whole-body metabolism through secreted factors. GDF15 and FGF21 are widely studied mitochondrial stress-related secreted factors and are often induced by ISR/ATF4-related programs.

GDF15 is commonly associated with mitochondrial diseases, metabolic stress, inflammation, and tumor cachexia. FGF21 is closely related to metabolic regulation in the liver, adipose tissue, and skeletal muscle. Both can serve as systemic readouts of mitochondrial stress, but neither should be simply equated with activation of a single pathway.

5.2 Mitochondrial-Derived Peptides

Mitochondrial-derived peptides (MDPs) are short peptides encoded by the mitochondrial genome or related small open reading frames, including Humanin and MOTS-c. They participate in metabolic regulation, stress protection, inflammatory regulation, and aging-related processes.

Exercise, energy stress, and mitochondrial functional changes can affect the expression of some MDPs. The significance of MDPs lies in linking mitochondrial status with inter-tissue communication, metabolic adaptation, and aging regulation.

5.3 Research Value of Mitochondrial Factors

Factor Type	Representative Molecules	Main Significance
ISR-induced secreted factors	GDF15	Reflects mitochondrial stress, metabolic pressure, and disease burden
Metabolic regulatory factors	FGF21	Participates in metabolic adaptation in liver, adipose tissue, and skeletal muscle
Mitochondrial-derived peptides	Humanin, MOTS-c	Connects mitochondrial function with systemic protective responses
Inflammation-related signals	mtDNA, N-formyl peptides	Trigger immune recognition and inflammatory responses
Metabolic signals	NAD⁺/NADH, lactate, TCA intermediates	Affect epigenetics, metabolic remodeling, and cell fate

6 Mitochondrial Stress, Inflammation, and Immunity

6.1 mtDNA Release and Innate Immune Activation

Mitochondria originate from an endosymbiotic process, and their DNA and some molecular structures have bacteria-like immunostimulatory features. When mitochondrial membrane integrity decreases or mitochondrial clearance is impaired, mtDNA can enter the cytosol or extracellular environment and activate cGAS-STING, TLR9, or inflammasome-related pathways.

This response is important in infection, tissue injury, autoimmune diseases, neuroinflammation, and aging-related chronic inflammation.

6.2 Mitochondrial ROS and Inflammatory Amplification

Mitochondrial ROS can function as signaling molecules, but excessive ROS can also cause oxidative damage. Moderate ROS can trigger protective mitohormesis, whereas persistently high ROS promotes activation of NF-κB, the NLRP3 inflammasome, lipid peroxidation, and cell death pathways.

The role of mitochondrial ROS must be interpreted according to intensity and duration. Simply treating ROS as “harmful products” is inaccurate. In certain adaptive contexts, low-level ROS are important signals for stress-protective responses.

7 Roles of Mitochondrial Stress in Disease

7.1 Aging and Age-Related Diseases

Mild mitochondrial stress can enhance antioxidant defense, proteostasis, and metabolic adaptation through mitohormesis, potentially delaying some age-related functional decline. Metformin, exercise, caloric restriction, and some mitochondrial quality control regulators are all related to this concept.

However, long-term mitochondrial functional decline leads to energy insufficiency, proteostasis stress, ROS elevation, inflammatory activation, and increased cellular senescence. Therefore, aging research needs to distinguish short-term adaptive stress from long-term degenerative damage.

7.2 Tumors

Tumor cells are often exposed to hypoxia, nutrient deprivation, oxidative stress, and metabolic reprogramming. UPRmt, the ISR, and mitochondrial quality control can help tumor cells adapt to these stresses and enhance survival, invasion, metastasis, and therapeutic tolerance.

In some tumors, elevated UPRmt gene signatures are associated with poor prognosis. Mitochondrial protein quality control molecules such as HSP60, LONP1, and CLPP may also support tumor cell survival. Unlike anti-aging strategies, inhibiting certain mitochondrial adaptive stress pathways may have therapeutic value in tumors.

7.3 Neurodegenerative Diseases

Neurons are highly dependent on energy supply, proteostasis, and mitochondrial transport. Abnormal mitochondrial stress can cause insufficient synaptic energy supply, axonal transport defects, ROS elevation, protein aggregation, and neuroinflammation. Mitochondrial quality control and abnormal stress signaling are important in diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis.

PINK1/Parkin-mediated mitophagy defects, abnormal mitochondrial protein import, and mtDNA release may all participate in neurodegenerative pathology. In these diseases, appropriately enhancing mitochondrial quality control may be protective, but excessive ISR activation may suppress neuronal protein synthesis and functional maintenance.

7.4 Metabolic Diseases

The liver, skeletal muscle, adipose tissue, and pancreatic β cells all depend on mitochondria to maintain energy homeostasis. Mitochondrial stress can induce FGF21, GDF15, AMPK, and ISR-related responses and participate in regulating lipid metabolism, insulin sensitivity, inflammation, and energy expenditure.

In fatty liver disease, obesity, and type 2 diabetes, mitochondrial stress may be a consequence of excessive metabolic load, but may also temporarily maintain tissue function through metabolic adaptation. Its role should be judged according to tissue type, time window, and metabolic phenotype.

7.5 Cardiovascular Diseases

Cardiomyocytes have high energy demands and are highly sensitive to mitochondrial function. Ischemia-reperfusion, heart failure, and cardiac hypertrophy can all trigger mitochondrial stress, ROS elevation, calcium homeostasis disturbance, and abnormal mitochondrial quality control. Moderate activation of mitochondrial protective programs may reduce injury, but persistent stress drives cardiomyocyte death and functional decline.

Disease Type	Mitochondrial Stress Feature	Possible Role
Aging	Mild ROS, proteostasis pressure, quality control changes	Short-term protection and long-term decline
Tumors	Enhanced UPRmt/ISR and metabolic adaptation	Supports survival, metastasis, and drug resistance
Neurodegenerative diseases	Protein import defects, abnormal mitophagy, ROS elevation	Promotes synaptic and neuronal functional injury
Metabolic diseases	Elevated FGF21/GDF15 and abnormal oxidative metabolism	Metabolic adaptation or pathological remodeling
Cardiovascular diseases	Ischemia-reperfusion, ROS, and calcium homeostasis abnormalities	Affects myocardial injury and repair

8 Common Questions and Result Interpretation

8.1 Does ATF4 Elevation Equal Mitochondrial ISR Activation?

No. ATF4 is a shared downstream factor of the ISR. Amino acid deprivation, ER stress, oxidative stress, and viral infection can also induce ATF4. To demonstrate mitochondria-derived ISR activation, DELE1, HRI, OMA1, mitochondrial membrane potential, and respiratory chain functional changes should be evaluated together.

8.2 Can GDF15 and FGF21 Serve as Specific Markers of Mitochondrial Stress?

GDF15 and FGF21 can serve as mitochondrial stress-related secretory readouts, but they are not absolutely specific. Inflammation, nutritional status, tumor burden, tissue injury, and metabolic diseases can also affect their expression. A more reasonable approach is to use them as systemic stress indicators and analyze them together with intracellular pathway markers and functional readouts.

8.3 Is UPRmt Activation Always Protective?

Not necessarily. Short-term UPRmt activation helps restore mitochondrial proteostasis, but in tumors it may enhance cellular adaptation to stress, metastasis, and drug resistance. In degenerative diseases, persistent UPRmt may indicate long-term mitochondrial pressure and does not necessarily represent functional recovery.

8.4 Is Increased Mitochondrial ROS Always Harmful?

Not necessarily. Low-level and transient ROS can serve as signals that trigger mitohormesis and adaptive protection. High-level and persistent ROS can damage lipids, proteins, and DNA and promote inflammation and cell death. ROS results should be interpreted together with dose, duration, and functional phenotype.

8.5 Does Inhibiting Mitochondrial Stress Pathways Always Have Therapeutic Value?

No universal conclusion can be made. In tumors, inhibiting UPRmt or mitochondrial quality control may weaken cancer cell adaptability. However, in neurodegenerative diseases, myocardial injury, or aging-related functional decline, moderately enhancing mitochondrial protective responses may be more beneficial. Therapeutic strategies must depend on disease context and stress stage.

9 Product Selection Related to Mitochondrial Stress Signaling and Disease Research

Product Module	Cat. No.	Product Name	Grade & Purity	Application Positioning
Mitochondrial membrane potential detection	M1508380	Mitochondrial Membrane Potential Assay Kit (JC-1)	BioReagent, suitable for fluorescence analysis, molecular biology grade	Detects mitochondrial membrane potential decline; suitable for evaluating early mitochondrial injury and stress activation
Mitochondrial membrane potential detection	J125134	JC-1	≥95%	Used for fluorescent detection of mitochondrial membrane potential and can be combined with flow cytometry or fluorescence microscopy
Mitochondrial membrane potential detection	M1509036	Mitochondrial Membrane Potential Assay Kit (JC-10)	BioReagent	JC-1 alternative membrane potential detection system, suitable for analyzing mitochondrial functional changes
Mitochondrial ROS detection	M647069	MitoSOX Red	≥95%	Detects mitochondrial superoxide and connects mitochondrial ROS, oxidative stress, and inflammatory responses
Mitochondrial ROS detection	M1508403	Mitochondrial Superoxide Assay Kit (MitoSOX Red)	Suitable for immunofluorescence (IF), BioReagent, biological stain, for microscopy	Used for cellular mitochondrial ROS imaging and evaluation of mitochondrial oxidative stress
Energy metabolism detection	R1375244	ATP Determination Kit	BioReagent, ready-to-use, for chemiluminescence	Evaluates cellular ATP levels and assists in assessing cellular energy status; oxidative phosphorylation function should be interpreted together with oxygen consumption rate, respiratory chain activity, or mitochondrial membrane potential
Energy metabolism detection	A1508155	Enhanced ATP Assay Kit	BioReagent, for chemiluminescence	Used for higher-sensitivity ATP detection, suitable for mitochondrial functional injury models
Mitochondrial stress induction	C1509561	CCCP solution (10mmol/L)	BioReagent, 10 mmol/L	Disrupts mitochondrial membrane potential and is commonly used for PINK1/Parkin mitophagy and mitochondrial stress models
Mitochondrial stress induction	C303974	Carbonyl cyanide 3-chlorophenylhydrazone (CCCP)	Moligand™, ≥98%	Mitochondrial uncoupler used to induce membrane potential loss and mitochondrial quality control responses
ISR transcriptional response	EJ1513289	Mouse Activating Transcription Factor 4 (ATF4) ELISA Kit	BioReagent	Detects ATF4 levels and assists in evaluating downstream ISR transcriptional responses; mitochondria-derived ISR should be interpreted together with DELE1, HRI, OMA1, eIF2α phosphorylation, and mitochondrial functional changes
Sustained ISR/injury response	Ab099377	Recombinant DDIT3 Antibody	Recombinant, ExactAb™, validated, 0.3 mg/mL	Detects CHOP/DDIT3 and determines whether sustained ISR shifts toward injury or cell death-related programs
Mitochondrial stress secreted factor	EJ1514294	Human Growth Differentiation Factor 15 (GDF15) ELISA Kit	BioReagent	Detects GDF15 in human-derived samples; suitable for evaluating mitochondrial stress in disease models, serum, or tissue samples
Mitochondrial stress secreted factor	EJ1512880	Mouse Growth Differentiation Factor 15 (GDF15) ELISA Kit	BioReagent	Detects mouse GDF15; suitable for analyzing mitochondrial stress and systemic responses in animal models
Metabolic stress secreted factor	EJ1512795	Mouse Fibroblast Growth Factor 21 (FGF21) ELISA Kit	BioReagent	Detects FGF21 and evaluates mitochondrial metabolic stress, liver/muscle adaptation, and systemic metabolic responses
UPRmt chaperone protein	Ab326448	Hsp60 Antibody	Knockdown validated	Detects HSP60 and assists in evaluating mitochondrial matrix protein-folding stress; UPRmt activation should be interpreted together with LONP1, CLPP, ATF5, CHOP/ATF4, and mitochondrial functional readouts
UPRmt detection	EJ1515192	Mouse Heat Shock Protein 60 (Hsp60) ELISA Kit	BioReagent	Quantitatively detects mouse HSP60; suitable for evaluating UPRmt and mitochondrial proteostasis in animal models
UPRmt protein quality control	Ab113406	LONP1/Lon Antibody	ExactAb™, validated, 1.0 mg/mL	Detects the mitochondrial matrix protease LONP1 and analyzes abnormal mitochondrial protein quality control
UPRmt protein quality control	Ab096915	Recombinant CLPP Antibody	Recombinant, ExactAb™, knockdown validated, validated, see COA	Detects CLPP; suitable for UPRmt, mitochondrial protease system, and tumor mitochondrial dependency research
Mitochondrial morphology/quality marker	Ab131951	Recombinant TOMM20 Antibody	Recombinant, ExactAb™, validated, 0.3 mg/mL	Labels the mitochondrial outer membrane and analyzes mitochondrial morphology and distribution; mitophagic degradation should be interpreted together with LC3, p62, PINK1/Parkin, or lysosomal colocalization markers
Mitophagy initiation	EJ1513577	Human PTEN Induced Putative Kinase 1 (PINK1) ELISA Kit	BioReagent	Detects PINK1 levels and assists in evaluating PINK1-related mitophagy changes; mitophagy initiation after mitochondrial membrane potential decline should be interpreted together with mitochondrial PINK1 accumulation, Parkin recruitment, or mitochondria-lysosome colocalization

Mitochondrial stress signaling connects organelle injury, proteostasis, redox regulation, and systemic metabolic responses. The OMA1-DELE1-HRI-ATF4 axis, UPRmt, PINK1/Parkin-mediated mitophagy, and mitochondrial factors such as GDF15 and FGF21 are core nodes for understanding the relationship between mitochondrial stress and disease.

For more related articles, please see below:

[1] Oxidative Stress and Experimental Interpretation Framework for ROS, JC-1, MPTP, and Calcium Indicators in Mitochondrial Function Assessment