Invest Clin 65(2): 230 - 252, 2024 https://doi.org/10.54817/IC.v65n2a09

Corresponding Author: Diego Fernández-Lázaro. Department of Cellular Biology, Genetics, Histology

and Pharmacology, Faculty of Health Sciences, University of Valladolid, Campus of Soria, Soria, Spain.

E-mail: diego.fernadez.lazaro@uva.es

Mechanisms of programmed cell death:

structural and functional pathways.

A narrative review.

Diego Fernández-Lázaro

1,2,3

Begoña Sanz

4,5

and Jesús Seco-Calvo

3,4,6

Department of Cellular Biology, Genetics, Histology and Pharmacology, Faculty

of Health Sciences, University of Valladolid, Campus of Soria, Soria, Spain.

Neurobiology Research Group, Faculty of Medicine, University of Valladolid, Valladolid,

Spain.

SARCELLOMICS® Research Group, León, Spain.

Department of Physiology, University of the Basque Country, Leioa, Spain.

Biocruces Bizkaia Health Research Institute, Barakaldo Spain.

Institute of Biomedicine, University of León, León, Spain.

Keywords: apoptosis; caspases; mitochondrial/intrinsic pathway; extrinsic pathway;

necroptosis; autophagy.

Abstract. Apoptosis, necroptosis, and autophagy are cellular mechanisms

by which cells are programmed to die under various physiological and devel-

opmental stimuli. A multitude of protein mediators of programmed cell death

have been identified, and apoptosis, necroptosis, and autophagy signals have

been found to utilize common pathways that elucidate the proteins involved.

This narrative review focuses on caspase-dependent and caspase-independent

programmed cell death systems. Including studies of caspase-dependent pro-

grammed cell death, extrinsic pathway apoptotic mechanisms, phosphatidyl-

serine (PS), FAS (APO-1/CD95), tumor necrosis factor (TNF) receptor type

1 (TNF-R1) and TNF-related apoptosis-inducing ligand (TRAIL), and intrinsic

or mitochondrial pathway such as cytochrome C, the Bcl-2 family of proteins

and Smac/Diablo. The Bcl-2 family has apoptotic mediators Bcl-2-associated X

protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), Bcl-2-interacting

protein BIM (Bim), Bcl-2 agonist of cell death (Bad), Bid, Bcl-2 adenovirus E1B

19kDa-interacting protein 1 NIP3 (Bnip3), BMF, HRK, Noxa and PUMA and an-

tiapoptotic proteins such as Bcl-2 itself, Mcl-1, Bcl-w, A1, and Bcl-XL. Moreover,

caspase-independent programmed cell death pathways include the mitochon-

drial pathway with the protein mediators apoptosis inducing factor (AIF) and

endonuclease G, and the pathways necroptosis, and autophagy. Understanding

programmed cell death from those reported in this review could shed substan-

Mechanisms of programmed cell death. A narrative review 231

Vol. 65(2): 230 - 252, 2024

Mecanismos de muerte celular programada: vías estructurales

y funcionales. Una revisión narrativa.

Invest Clin 2024; 65 (2): 230 – 252

Palabras clave: apoptosis; caspasas; vía mitocondrial/intrínseca; vía extrínseca;

necroptosis; autofagia.

Resumen. La apoptosis, la necroptosis y la autofagia son mecanismos celu-

lares mediante los cuales las células se programan para morir bajo una amplia

gama de estímulos fisiológicos. Esta revisión describe en los sistemas de muerte

celular programada dependientes e independientes de la caspasa. Los estudios

incluidos sobre la muerte celular programada dependiente de la caspasa inclu-

yen mecanismos apoptóticos de la vía extrínseca que incluyen fosfatidilserina

(PS), FAS (APO-1/CD95), receptor del factor de necrosis tumoral (FNT) tipo

1 (FNT-R1) e inductor de la apoptosis relacionada con ligando FNT (TRAIL)

y vía intrínseca o mitocondrial como el citocromo C, la familia de proteínas

Bcl-2 y Smac/Diablo. La familia Bcl-2 tiene mediadores apoptóticos, proteína

X asociada a Bcl-2 (Bax) y antagonista/asesino homólogo de Bcl-2 (Bak), pro-

teína BIM que interactúa con Bcl-2 (Bim), agonista de la muerte celular de

Bcl-2 (Bad), Bid, proteína 1 que interactúa con el adenovirus E1B 19kDa de

Bcl-2, NIP3 (Bnip3), BMF, HRK, Noxa y PUMA y proteínas antiapoptóticas como

la propia Bcl-2, Mcl-1, Bcl-w, A1 y Bcl-XL. Además, las vías de muerte celular

programada independientes de la caspasa incluyen la vía mitocondrial con los

mediadores proteicos factor inductor de apoptosis (FIA) y endonucleasa G, las

vías necroptosis y autofagia. Comprender la muerte celular programada a partir

de los contenidos descritos en esta revisión podría arrojar luz sustancial sobre

los procesos de la homeostasis biológica y podría proporcionar la capacidad de

modular la respuesta de muerte celular programada y conducir a nuevas inter-

venciones terapéuticas en una amplia gama de enfermedades.

Received: 19-10-2023 Accepted: 18-11-2023

INTRODUCTION

Every hour, billions of cells die in us,

and our tissues do not shrink because of a

natural regulation whereby cell death is

balanced by cell division. It is necessary to

control both death and cell division in dif-

ferentiated cells to balance the different cell

populations, avoiding affecting the adjacent

cells

The process in which cells eliminate

themselves in a controlled manner is called

tial light on the processes of biological homeostasis. In addition, identifying

specific proteins involved in these processes is mandatory to identify molecular

biomarkers and therapeutic targets. Furthermore, it could provide the ability to

modulate the programmed cell death response and could lead to new therapeu-

tic interventions in a disease.

232 Fernández-Lázaro et al.

Investigación Clínica 65(2): 2024

programmed cell death. Programmed cell

death plays an important role during em-

bryonic development, maintaining tissue

homeostasis in the body and eliminating

damaged cells

. In contrast, excessive or

defective cell death contributes to a broad

spectrum of human pathologies. Low-rate

cell death can result in the formation of

cancer and autoimmune diseases

, whereas

high-rate cell death can result in neurode-

generative disease, immunodeficiency, or

muscle atrophy

Knowledge of specific/differential pro-

teomic expression in each cell death is es-

sential for the early detection, diagnosis, and

prognosis of cell-death-related diseases. This

knowledge is also crucial for the use of more

precise and personalized pharmacological

treatments

. Cell death can be divided into

three groups: programmed, regulated, and

accidental

. Programmed cell death is pres-

ent in embryonic development and tissue

homeostasis, such as apoptosis and necrop-

tosis. Regulated cell death is that which, pro-

grammed or not, can be induced or inhibited

by a specific molecular mechanism through

pharmacology or genetic interventions, for

example, the release of neutrophil extracel-

lular traps (NETs), a regulated form of neu-

trophil cell death known as NETosis, modu-

lates neutrophil toxic effects. Accidental cell

death is triggered by external physical condi-

tions, such as ischemia, freeze-thaw cycles,

or high concentrations of pro-oxidants, an

example of this type of death are oncosis and

necrosis

. Two mechanisms of programmed

cell death are distinguished: apoptotic cell

death, dependent on caspases such as extrin-

sic and intrinsic apoptosis, and non-apoptot-

ic cell death, independent of caspases, such

as autophagy and necroptosis

MATERIALS AND METHODS

Search strategy

The present study is a narrative lit-

erature review comprising scientific stud-

ies conducted between May and July 2023

that sought to group and describe caspase-

dependent and caspase-independent pro-

grammed cell death, describing the molecu-

lar mechanisms of apoptosis, necroptosis,

and autophagy. The bibliographic search was

carried out in the following electronic data-

bases: Medline (PubMed), Sci-ELO, Scopus,

Science Direct, Cinahl, EMBASE - Excerpta

Medica Data Base, LILACS, Google Scholar,

Dialnet, and Cochrane Library Plus. The key-

words used for the search were: programmed

cell death, apoptosis, caspases, caspase in-

hibitory proteins, mitochondrial / intrinsic

pathway, extrinsic pathway, necroptosis, au-

tophagy, phosphatidylserine, FAS (APO-1/

CD95), tumor necrosis factor (TNF) recep-

tor type 1 (TNF-R1) and TNF-related apopto-

sis-inducing ligand (TRAIL) and cytochrome

C, linked by the Boolean operators “AND”

and “OR”. Additional records were gleaned

by conducting a ‘snowball’ search, checking

the reference lists of publications eligible

for full-text review, and using ResearchGate

to identify potential articles not included in

the databases used in the study.

Inclusion and exclusion criteria

The following inclusion criteria were

applied to select the articles: (1) Access to

the full text; (2) be a review, clinical trial,

observational study, or case report/study;

(3) identify caspase-dependent and cas-

pase-independent programmed cell death;

(4) describe the molecular mechanisms of

apoptosis, necroptosis, and autophagy; (6)

studies whose publication date is from the

beginning of the databases until July 2023;

(6) languages were restricted to English,

German, French, Italian, Spanish, and Por-

tuguese. The exclusion criteria applied were:

(2) Publications not related to programmed

cell death and/or describe its molecular

mechanisms; (2) duplicate documents.

Data extraction

After searching the databases for stud-

ies, the search titles were checked to iden-

tify duplicates and possible publications to